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Craig D. Logsdon - One of the best experts on this subject based on the ideXlab platform.

  • S100P: a novel therapeutic target for cancer
    Amino acids, 2010
    Co-Authors: Thiruvengadam Arumugam, Craig D. Logsdon
    Abstract:

    S100P expression is described in many different cancers, and its expression is associated with drug resistance, metastasis, and poor clinical outcome. S100P is member of the S100 family of small calcium-binding proteins that have been reported to have either intracellular or extracellular functions, or both. Extracellular S100P can bind with the receptor for advanced glycation end products (RAGE) and activate cellular signaling. Through RAGE, S100P has been shown to mediate tumor growth, drug resistance, and metastasis. S100P is specifically expressed in cancer cells in the adult. Therefore, S100P is a useful marker for differentiating cancer cells from normal cells, and can aid in the diagnosis of cancer by cytological examination. The expression of S100P in cancer cells has been related to hypomethylation of the gene. Multiple studies have confirmed the beneficial effects of blocking S100P/RAGE in cancer cells, and different blockers are being developed including small molecules and antagonist peptides. This review summarizes the role and significance of S100P in different cancers.

  • Effect of Cromolyn on S100P Interactions With RAGE and Pancreatic Cancer Growth and Invasion in Mouse Models
    Journal of the National Cancer Institute, 2006
    Co-Authors: Thiruvengadam Arumugam, Vijaya Ramachandran, Craig D. Logsdon
    Abstract:

    Despite recent advances in understanding the biology of pancreatic cancer and molecular alterations in tumor pathogenesis, pancreatic cancer remains an oncologic challenge, with a 5-year survival rate of less than 5%. Pancreatic adenocarcinoma is arguably the most lethal of all cancers, with more than 95% of patients diagnosed with the disease dying from it, more than half within 6 months. In the United States, it ranks fourth among the leading causes of cancer death, accounting for more than 30 000 deaths annually (1). There is no effective therapy for pancreatic cancer other than early resection, but only a small percentage of patients are good candidates for surgery. Gemcitabine is the current conventional chemotherapy for pancreatic cancer, and it provides meager benefits (2). Combinations of gemcitabine with radiation or with other cytotoxic agents have also proven disappointing. Because of the poor response to these standard forms of therapy, recent efforts have focused on the application of novel, biologically targeted agents aimed at well-known cancer mechanisms. Examples of these approaches include compounds that target vascular endothelial growth factor receptors, e.g., bevacizumab; the epidermal growth factor receptor (EGFR), e.g., cetuximab; the EGFR-activating tyrosine kinase, e.g., erlotinib and gefitinib; and K-ras, e.g., farnesyol transferase inhibitor tipifarnib. However, most of the early clinical trials with the newer agents have shown no (2, 3) or only very modest (4) survival advantage compared with standard gemcitabine treatment. Clearly, new targets and therapeutic approaches are needed for this disease. Therapeutic target development requires identification of novel molecules, validation of their functional importance, understanding their mechanisms of action, and strategies for intervention. S100P has recently been found to be overexpressed in pancreatic (5–7), breast (8), and lung (9) cancers. S100P is a 95-amino acid member of the S100 family of proteins (10). S100P is functionally important for pancreatic cancer cell growth and survival, in that we previously observed that levels of cellular S100P affect the rate of tumor growth in vivo and resistance of pancreatic cancer cells against 5-fluorouracil treatment in vitro (11). In colon cancer cell lines, S100P levels are associated with resistance to chemotherapy (12). In lung cancer, S100P levels are associated with decreased patient survival (9). S100P is also associated with increased metastasis and decreased patient survival in breast cancer (8). Taken together, the evidence suggests that overexpressed S100P may increase tumor growth and metastasis and decrease patient survival. If so, blocking S100P function might improve responses to therapeutic treatments. The mechanisms of action of S100P have recently been elucidated in studies with pancreatic cancer cells. We found that S100P is secreted by pancreatic cancer cells and acts extracellularly through interactions with a cell surface protein receptor for advanced glycation end-products (RAGE) (13). RAGE is a multiligand receptor that interacts with a variety of molecules, including advanced glycation end-products, S100 molecules (S100B, S100A12, S100P), amyloid, and amphoterin (14). RAGE participates in a number of important pathologic processes, including Alzheimer’s disease, diabetes, inflammation, and cancer (14). Activation of RAGE by S100P stimulates several cellular signaling pathways, including the Mitogen-activated protein (MAP) kinase and nuclear factor-κ B (NFκB) pathways (13). NFκB signaling may be of particular importance because basal NFκB activity is elevated in the majority of pancreatic cancers (15) and elevated NFκB activity is associated with increased resistance to therapies (16, 17). Therefore, interventions that block the ability of S100P to activate RAGE may provide therapeutic benefit. In the current study, we focused on the effects of cromolyn (disodium 1,3-bis [(2 ′-carboxylatochromon-5 ′-yl)oxy]-2-hydroxypropane), an antiallergy compound (18) that has previously been shown to bind specifically to other members of the S100 protein family (S100A1, S100A12, S100A13) (19–21). We examined the interactions of cromolyn with S100P and its effects on S100P activation of RAGE. We then measured the consequences of these effects on cell proliferation, invasion, NFκB activity, and responses to gemcitabine using three pancreatic cancer cell lines BxPC-3 and MPanc-96 (which express endogenous S100P) and Panc-1 (which do not express S100P) and mouse models of pancreatic adenocarcinoma using these cell lines.

  • Cromolyn blocks S100P activation of RAGE, reduces pancreatic cancer growth and invasion and enhances gemcitabine chemotherapy
    Cancer Research, 2006
    Co-Authors: Thiruvengadam Arumugam, Vijaya Ramachandran, Craig D. Logsdon
    Abstract:

    Proc Amer Assoc Cancer Res, Volume 47, 2006 4625 Background: Pancreatic cancer remains an oncological challenge with a 5-year survival rate below 5%. Current therapies are unsatisfactory and patient outcome is dismal such that new treatments are desperately needed. Previously, we found that S100P is over expressed in more than 90% of pancreatic cancer, is secreted by cancer cells, activates the receptor for advanced glycation end-products (RAGE) and plays a major role in tumor growth and invasion (Clinical. Can. Res.2005 Aug 1;11(15):5356-64). Recent publications suggested that the anti-allergic drug cromolyn might interact with S100 molecules. Therefore, in the current study we sought to examine the ability of cromolyn to bind with S100P and inhibit its interactions with RAGE and its effects on pancreatic cancer. Methods: A cromolyn drug affinity column was used to determine the interaction between S100P and cromolyn. The ability of cromolyn to interfere with the interaction of S100P with its receptor RAGE was analyzed by co-immunoprecipitation studies. Cancer cell growth and invasion were analyzed with cells without endogenous S100P (Panc-1) and also cells with endogenous S100P (BxPc3 and Mpanc-96) in vitro and in vivo . In orthotopic tumor models, cromolyn (5mg/k.g.b.wt/daily by i.p.) was administered with and without gemcitabine (125mg/k.g.bt/twice a month) and tumor growth and invasion were monitored using bioluminescence imaging every week for six weeks. Results: S100P was retained by a cromolyn drug affinity column, indicating a direct interaction between these molecules. Cromolyn also blocked the interaction of S100P and RAGE in co-immunoprecipitation experiments. In vitro , cromolyn inhibited the growth and invasiveness of pancreatic cancer cells with endogenous S100P (BxPc3 and Mpanc-96), but not Panc-1 cells that lack endogenous S100P. In orthotopic tumor models, cromolyn treatment significantly reduced the growth and metastasis of tumors developed from S100P expressing cancer cells (BxPc3 and Mpanc-96) but not cancer cells lacking S100P (Panc-1). Cromolyn also enhanced the efficiency of gemcitabine and effects of the combination were greater than either drug alone. The combination resulted in a dramatic reduction in tumor growth (BxPc3 and Mpanc-96) and the almost complete absence of metastasis to liver and lung. Conclusion: Our findings suggest that cromolyn, through its ability to interfere with S100P activation of RAGE, inhibits pancreatic cancer growth and metastasis and increases the efficiency of chemotherapy. Thus, cromolyn treatments should be considered to enhance standard chemotherapy for pancreatic cancer.

  • S100P stimulates cell proliferation and survival via receptor for activated glycation end products rage
    Journal of Biological Chemistry, 2004
    Co-Authors: Thiruvengadam Arumugam, Diane M Simeone, Ann Marie Schmidt, Craig D. Logsdon
    Abstract:

    Abstract S100P is a member of the S100 protein family that is expressed in several malignant neoplasms. Currently the effects of this molecule on cell function are unknown. In the present study we investigated the biological effects and mechanisms of action of S100P using NIH3T3 cells. Expression of S100P in NIH3T3 cells led to the presence of S100P in the culture medium, increased cellular proliferation, and enhanced survival after detachment from the culture substrate or after exposure to the chemotherapeutic agent 5-flurouracil. The proliferation and survival effects of S100P expression were duplicated in a time- and concentration-dependent manner by the extracellular addition of purified S100P to wild-type NIH3T3 cells and correlated with the activation of extracellular-regulated kinases (Erks) and NF-κB. To determine the mechanisms involved in these effects, we tested the hypothesis that S100P activated RAGE (receptor for activated glycation end products). We found that S100P co-immunoprecipitated with RAGE. Furthermore, the effects of S100P on cell signaling, proliferation, and survival were blocked by agents that interfere with RAGE including administration of an amphoterin-derived peptide known to antagonize RAGE activation, anti-RAGE antibodies, and by expression of a dominant negative RAGE. These data suggest that S100P can act in an autocrine manner via RAGE to stimulate cell proliferation and survival.

Adriana Gibadulinova - One of the best experts on this subject based on the ideXlab platform.

  • cancer associated S100P protein binds and inactivates p53 permits therapy induced senescence and supports chemoresistance
    Oncotarget, 2016
    Co-Authors: Adriana Gibadulinova, Michal Pastorek, Pavel Filipcik, Peter Radvak, Lucia Csaderova, Borivoj Vojtesek, Silvia Pastorekova
    Abstract:

    // Adriana Gibadulinova 1 , Michal Pastorek 2 , Pavel Filipcik 1 , Peter Radvak 1 , Lucia Csaderova 1 , Borivoj Vojtesek 2 , Silvia Pastorekova 1, 2 1 Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic 2 Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic Correspondence to: Silvia Pastorekova, e-mail: silvia.pastorekova@savba.sk Keywords: S100P calcium-binding protein, p53 tumor suppressor, HDM2, cell death, therapy-induced senescence Received: September 09, 2015     Accepted: February 20, 2016     Published: March 9, 2016 ABSTRACT S100P belongs to the S100 family of calcium-binding proteins regulating diverse cellular processes. Certain S100 family members (S100A4 and S100B) are associated with cancer and used as biomarkers of metastatic phenotype. Also S100P is abnormally expressed in tumors and implicated in migration-invasion, survival, and response to therapy. Here we show that S100P binds the tumor suppressor protein p53 as well as its negative regulator HDM2, and that this interaction perturbs the p53-HDM2 binding and increases the p53 level. Paradoxically, the S100P-induced p53 is unable to activate its transcriptional targets hdm2 , p21 WAF , and bax following the DNA damage. This appears to be related to reduced phosphorylation of serine residues in both N-terminal and C-terminal regions of the p53 molecule. Furthermore, the S100P expression results in lower levels of pro-apoptotic proteins, in reduced cell death response to cytotoxic treatments, followed by stimulation of therapy-induced senescence and increased clonogenic survival. Conversely, the S100P silencing suppresses the ability of cancer cells to survive the DNA damage and form colonies. Thus, we propose that the oncogenic role of S100P involves binding and inactivation of p53, which leads to aberrant DNA damage responses linked with senescence and escape to proliferation. Thereby, the S100P protein may contribute to the outgrowth of aggressive tumor cells resistant to cytotoxic therapy and promote cancer progression.

  • glucocorticoid receptor mediated transcriptional activation of S100P gene coding for cancer related calcium binding protein
    Journal of Cellular Biochemistry, 2011
    Co-Authors: Veronika Tothova, Silvia Pastorekova, Jaromir Pastorek, Jorma Isola, Seppo Parkkila, Juraj Kopacek, Adriana Gibadulinova
    Abstract:

    S100P is a member of the S100 family of calcium-binding proteins involved in calcium sensing and signal transduction. Its abnormal expression and biological activities are linked to tumor phenotype, namely to increased survival, proliferation, invasion and metastatic propensity of tumor cells. Association of S100P with outcome of tumor treatment and preliminary data from S100P promoter analysis prompted us to study regulation of S100P expression by glucocorticoids, which are implicated in tumor response to chemotherapy. We showed that dexamethasone (DX), a representative glucocorticoid, was capable to induce activity of S100P promoter by means of increased expression, nuclear translocation, and transactivation properties of the glucocorticoid receptor (GR). Moreover, DX treatment led to decreased phosphorylation of ERK1/2, reduced transcriptional activity of AP1, and modulated activity of some additional transcription factors. We identified a promoter region responsible for DX-mediated transactivation and proved GR binding to S100P promoter. We found that the effect of DX was enhanced by partial but not complete inhibition of the MAPK/ERK pathway, supporting an active crosstalk between GR and MAPK/ERK signal transduction in control of S100P expression. On the other hand, suppression of GR mRNA level by transient siRNA expression resulted in reduced S100P transcription. The role of GR activation in S100P regulation was supported by co-expression of GR with S100P in cells treated with DX. These data suggest that S100P is a direct transcriptional target of glucocorticoid-mediated signaling in tumor cells that is activated through the interplay of GR and MAPK pathways. J. Cell. Biochem. 112: 3373–3384, 2011. © 2011 Wiley Periodicals, Inc.

  • Glucocorticoid receptor‐mediated transcriptional activation of S100P gene coding for cancer‐related calcium‐binding protein
    Journal of cellular biochemistry, 2011
    Co-Authors: Veronika Tothova, Silvia Pastorekova, Jaromir Pastorek, Jorma Isola, Seppo Parkkila, Juraj Kopacek, Adriana Gibadulinova
    Abstract:

    S100P is a member of the S100 family of calcium-binding proteins involved in calcium sensing and signal transduction. Its abnormal expression and biological activities are linked to tumor phenotype, namely to increased survival, proliferation, invasion and metastatic propensity of tumor cells. Association of S100P with outcome of tumor treatment and preliminary data from S100P promoter analysis prompted us to study regulation of S100P expression by glucocorticoids, which are implicated in tumor response to chemotherapy. We showed that dexamethasone (DX), a representative glucocorticoid, was capable to induce activity of S100P promoter by means of increased expression, nuclear translocation, and transactivation properties of the glucocorticoid receptor (GR). Moreover, DX treatment led to decreased phosphorylation of ERK1/2, reduced transcriptional activity of AP1, and modulated activity of some additional transcription factors. We identified a promoter region responsible for DX-mediated transactivation and proved GR binding to S100P promoter. We found that the effect of DX was enhanced by partial but not complete inhibition of the MAPK/ERK pathway, supporting an active crosstalk between GR and MAPK/ERK signal transduction in control of S100P expression. On the other hand, suppression of GR mRNA level by transient siRNA expression resulted in reduced S100P transcription. The role of GR activation in S100P regulation was supported by co-expression of GR with S100P in cells treated with DX. These data suggest that S100P is a direct transcriptional target of glucocorticoid-mediated signaling in tumor cells that is activated through the interplay of GR and MAPK pathways. J. Cell. Biochem. 112: 3373–3384, 2011. © 2011 Wiley Periodicals, Inc.

  • Transcriptional regulation and functional implication of S100P in cancer
    Amino acids, 2010
    Co-Authors: Adriana Gibadulinova, Veronika Tothova, Jaromir Pastorek, Silvia Pastorekova
    Abstract:

    S100P is an EF-hand calcium-binding protein that was originally identified in placenta and subsequently associated with cancer. It is a member of S100 family of proteins that function as extracellular and/or intracellular regulators of diverse cellular processes and participate in various human pathologies. S100P expression was detected in a spectrum of human tumor cell lines and tissues derived from breast, prostate, pancreas, lung and colon, where it was connected with malignant phenotype, hormone independence and resistance to chemotherapy. Overexpression of S100P was shown to promote tumorigenesis and metastasis in diverse cancer models. Functional studies of S100P indicate that its biological activities are exerted through extracellular signaling via RAGE receptor, resulting in increased proliferation and survival, or through intracellular interaction with ezrin, leading to increased cell migration and metastasis. Molecular mechanisms regulating expression of S100P in cancer cells are just emerging. Besides earlier described DNA methylation, recent studies implicate bone morphogenic protein and non-steroidal anti-inflammatory drugs in control of S100P expression during tumor progression. Functional analysis of S100P promoter identified SMAD, STAT/CREB and SP/KLF binding sites as key regulatory elements participating in transcriptional activation of S100P gene in cancer cells. Moreover, the most recent data reveal that expression of S100P is up-regulated by activation of glucocorticoid receptor suggesting that S100P could play a role in therapy resistance mediated by glucocorticoids in solid tumors. Elucidation of S100P regulation is an important step towards understanding biological significance of its tissue distribution and proposing strategies for targeted S100P modulation.

  • Expression of S100P protein correlates with and contributes to the tumorigenic capacity of HeLa cervical carcinoma cells
    Oncology reports, 2005
    Co-Authors: Adriana Gibadulinova, Silvia Pastorekova, Juraj Kopacek, Monika Barathova, Alzbeta Hulikova, Richard Kettmann, Jaromir Pastorek
    Abstract:

    Tumor growth is associated with multiple changes at the gene expression level. Recognition of the genes differentially expressed between the cellular populations at various degrees of malignancy may provide valuable clues towards the identification of clinically useful diagnostic markers and/or therapeutic targets. In the present study, we used suppression subtractive PCR to identify differentially expressed genes with possible relevance for control of tumorigenic potential using two cervical carcinoma cell lines of the common HeLa origin, but of different capacity to generate tumors in nude mice. Screening of the subtracted libraries resulted in isolation of several known as well as novel genes including the gene encoding S100P calcium-binding protein that belongs to S100 family, whose members can bind and modulate effector proteins in a calcium-dependent manner. Expression of S100P was further studied in the context of different culture conditions and was found to correlate with the tumorigenic phenotype of the somatic cell hybrids between HeLa and normal human fibroblasts. Moreover, S100P was highly expressed in a number of tumorigenic cell lines derived from colorectal and breast carcinoma, suggesting that it is not restricted to a particular tumor type. Functional involvement of S100P in tumor growth was evaluated using tumor xenografts produced from the cells transfected with the full-length S100P cDNA. The results showed that S100P can positively affect anchorage-independent growth of the transfected cells and improve tumor formation in nude mice, suggesting that it actively participates in the control of the tumorigenic potential in vivo.

Silvia Pastorekova - One of the best experts on this subject based on the ideXlab platform.

  • cancer associated S100P protein binds and inactivates p53 permits therapy induced senescence and supports chemoresistance
    Oncotarget, 2016
    Co-Authors: Adriana Gibadulinova, Michal Pastorek, Pavel Filipcik, Peter Radvak, Lucia Csaderova, Borivoj Vojtesek, Silvia Pastorekova
    Abstract:

    // Adriana Gibadulinova 1 , Michal Pastorek 2 , Pavel Filipcik 1 , Peter Radvak 1 , Lucia Csaderova 1 , Borivoj Vojtesek 2 , Silvia Pastorekova 1, 2 1 Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic 2 Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic Correspondence to: Silvia Pastorekova, e-mail: silvia.pastorekova@savba.sk Keywords: S100P calcium-binding protein, p53 tumor suppressor, HDM2, cell death, therapy-induced senescence Received: September 09, 2015     Accepted: February 20, 2016     Published: March 9, 2016 ABSTRACT S100P belongs to the S100 family of calcium-binding proteins regulating diverse cellular processes. Certain S100 family members (S100A4 and S100B) are associated with cancer and used as biomarkers of metastatic phenotype. Also S100P is abnormally expressed in tumors and implicated in migration-invasion, survival, and response to therapy. Here we show that S100P binds the tumor suppressor protein p53 as well as its negative regulator HDM2, and that this interaction perturbs the p53-HDM2 binding and increases the p53 level. Paradoxically, the S100P-induced p53 is unable to activate its transcriptional targets hdm2 , p21 WAF , and bax following the DNA damage. This appears to be related to reduced phosphorylation of serine residues in both N-terminal and C-terminal regions of the p53 molecule. Furthermore, the S100P expression results in lower levels of pro-apoptotic proteins, in reduced cell death response to cytotoxic treatments, followed by stimulation of therapy-induced senescence and increased clonogenic survival. Conversely, the S100P silencing suppresses the ability of cancer cells to survive the DNA damage and form colonies. Thus, we propose that the oncogenic role of S100P involves binding and inactivation of p53, which leads to aberrant DNA damage responses linked with senescence and escape to proliferation. Thereby, the S100P protein may contribute to the outgrowth of aggressive tumor cells resistant to cytotoxic therapy and promote cancer progression.

  • glucocorticoid receptor mediated transcriptional activation of S100P gene coding for cancer related calcium binding protein
    Journal of Cellular Biochemistry, 2011
    Co-Authors: Veronika Tothova, Silvia Pastorekova, Jaromir Pastorek, Jorma Isola, Seppo Parkkila, Juraj Kopacek, Adriana Gibadulinova
    Abstract:

    S100P is a member of the S100 family of calcium-binding proteins involved in calcium sensing and signal transduction. Its abnormal expression and biological activities are linked to tumor phenotype, namely to increased survival, proliferation, invasion and metastatic propensity of tumor cells. Association of S100P with outcome of tumor treatment and preliminary data from S100P promoter analysis prompted us to study regulation of S100P expression by glucocorticoids, which are implicated in tumor response to chemotherapy. We showed that dexamethasone (DX), a representative glucocorticoid, was capable to induce activity of S100P promoter by means of increased expression, nuclear translocation, and transactivation properties of the glucocorticoid receptor (GR). Moreover, DX treatment led to decreased phosphorylation of ERK1/2, reduced transcriptional activity of AP1, and modulated activity of some additional transcription factors. We identified a promoter region responsible for DX-mediated transactivation and proved GR binding to S100P promoter. We found that the effect of DX was enhanced by partial but not complete inhibition of the MAPK/ERK pathway, supporting an active crosstalk between GR and MAPK/ERK signal transduction in control of S100P expression. On the other hand, suppression of GR mRNA level by transient siRNA expression resulted in reduced S100P transcription. The role of GR activation in S100P regulation was supported by co-expression of GR with S100P in cells treated with DX. These data suggest that S100P is a direct transcriptional target of glucocorticoid-mediated signaling in tumor cells that is activated through the interplay of GR and MAPK pathways. J. Cell. Biochem. 112: 3373–3384, 2011. © 2011 Wiley Periodicals, Inc.

  • Glucocorticoid receptor‐mediated transcriptional activation of S100P gene coding for cancer‐related calcium‐binding protein
    Journal of cellular biochemistry, 2011
    Co-Authors: Veronika Tothova, Silvia Pastorekova, Jaromir Pastorek, Jorma Isola, Seppo Parkkila, Juraj Kopacek, Adriana Gibadulinova
    Abstract:

    S100P is a member of the S100 family of calcium-binding proteins involved in calcium sensing and signal transduction. Its abnormal expression and biological activities are linked to tumor phenotype, namely to increased survival, proliferation, invasion and metastatic propensity of tumor cells. Association of S100P with outcome of tumor treatment and preliminary data from S100P promoter analysis prompted us to study regulation of S100P expression by glucocorticoids, which are implicated in tumor response to chemotherapy. We showed that dexamethasone (DX), a representative glucocorticoid, was capable to induce activity of S100P promoter by means of increased expression, nuclear translocation, and transactivation properties of the glucocorticoid receptor (GR). Moreover, DX treatment led to decreased phosphorylation of ERK1/2, reduced transcriptional activity of AP1, and modulated activity of some additional transcription factors. We identified a promoter region responsible for DX-mediated transactivation and proved GR binding to S100P promoter. We found that the effect of DX was enhanced by partial but not complete inhibition of the MAPK/ERK pathway, supporting an active crosstalk between GR and MAPK/ERK signal transduction in control of S100P expression. On the other hand, suppression of GR mRNA level by transient siRNA expression resulted in reduced S100P transcription. The role of GR activation in S100P regulation was supported by co-expression of GR with S100P in cells treated with DX. These data suggest that S100P is a direct transcriptional target of glucocorticoid-mediated signaling in tumor cells that is activated through the interplay of GR and MAPK pathways. J. Cell. Biochem. 112: 3373–3384, 2011. © 2011 Wiley Periodicals, Inc.

  • Transcriptional regulation and functional implication of S100P in cancer
    Amino acids, 2010
    Co-Authors: Adriana Gibadulinova, Veronika Tothova, Jaromir Pastorek, Silvia Pastorekova
    Abstract:

    S100P is an EF-hand calcium-binding protein that was originally identified in placenta and subsequently associated with cancer. It is a member of S100 family of proteins that function as extracellular and/or intracellular regulators of diverse cellular processes and participate in various human pathologies. S100P expression was detected in a spectrum of human tumor cell lines and tissues derived from breast, prostate, pancreas, lung and colon, where it was connected with malignant phenotype, hormone independence and resistance to chemotherapy. Overexpression of S100P was shown to promote tumorigenesis and metastasis in diverse cancer models. Functional studies of S100P indicate that its biological activities are exerted through extracellular signaling via RAGE receptor, resulting in increased proliferation and survival, or through intracellular interaction with ezrin, leading to increased cell migration and metastasis. Molecular mechanisms regulating expression of S100P in cancer cells are just emerging. Besides earlier described DNA methylation, recent studies implicate bone morphogenic protein and non-steroidal anti-inflammatory drugs in control of S100P expression during tumor progression. Functional analysis of S100P promoter identified SMAD, STAT/CREB and SP/KLF binding sites as key regulatory elements participating in transcriptional activation of S100P gene in cancer cells. Moreover, the most recent data reveal that expression of S100P is up-regulated by activation of glucocorticoid receptor suggesting that S100P could play a role in therapy resistance mediated by glucocorticoids in solid tumors. Elucidation of S100P regulation is an important step towards understanding biological significance of its tissue distribution and proposing strategies for targeted S100P modulation.

  • Expression of S100P protein correlates with and contributes to the tumorigenic capacity of HeLa cervical carcinoma cells
    Oncology reports, 2005
    Co-Authors: Adriana Gibadulinova, Silvia Pastorekova, Juraj Kopacek, Monika Barathova, Alzbeta Hulikova, Richard Kettmann, Jaromir Pastorek
    Abstract:

    Tumor growth is associated with multiple changes at the gene expression level. Recognition of the genes differentially expressed between the cellular populations at various degrees of malignancy may provide valuable clues towards the identification of clinically useful diagnostic markers and/or therapeutic targets. In the present study, we used suppression subtractive PCR to identify differentially expressed genes with possible relevance for control of tumorigenic potential using two cervical carcinoma cell lines of the common HeLa origin, but of different capacity to generate tumors in nude mice. Screening of the subtracted libraries resulted in isolation of several known as well as novel genes including the gene encoding S100P calcium-binding protein that belongs to S100 family, whose members can bind and modulate effector proteins in a calcium-dependent manner. Expression of S100P was further studied in the context of different culture conditions and was found to correlate with the tumorigenic phenotype of the somatic cell hybrids between HeLa and normal human fibroblasts. Moreover, S100P was highly expressed in a number of tumorigenic cell lines derived from colorectal and breast carcinoma, suggesting that it is not restricted to a particular tumor type. Functional involvement of S100P in tumor growth was evaluated using tumor xenografts produced from the cells transfected with the full-length S100P cDNA. The results showed that S100P can positively affect anchorage-independent growth of the transfected cells and improve tumor formation in nude mice, suggesting that it actively participates in the control of the tumorigenic potential in vivo.

Thiruvengadam Arumugam - One of the best experts on this subject based on the ideXlab platform.

  • S100P: a novel therapeutic target for cancer
    Amino acids, 2010
    Co-Authors: Thiruvengadam Arumugam, Craig D. Logsdon
    Abstract:

    S100P expression is described in many different cancers, and its expression is associated with drug resistance, metastasis, and poor clinical outcome. S100P is member of the S100 family of small calcium-binding proteins that have been reported to have either intracellular or extracellular functions, or both. Extracellular S100P can bind with the receptor for advanced glycation end products (RAGE) and activate cellular signaling. Through RAGE, S100P has been shown to mediate tumor growth, drug resistance, and metastasis. S100P is specifically expressed in cancer cells in the adult. Therefore, S100P is a useful marker for differentiating cancer cells from normal cells, and can aid in the diagnosis of cancer by cytological examination. The expression of S100P in cancer cells has been related to hypomethylation of the gene. Multiple studies have confirmed the beneficial effects of blocking S100P/RAGE in cancer cells, and different blockers are being developed including small molecules and antagonist peptides. This review summarizes the role and significance of S100P in different cancers.

  • Effect of Cromolyn on S100P Interactions With RAGE and Pancreatic Cancer Growth and Invasion in Mouse Models
    Journal of the National Cancer Institute, 2006
    Co-Authors: Thiruvengadam Arumugam, Vijaya Ramachandran, Craig D. Logsdon
    Abstract:

    Despite recent advances in understanding the biology of pancreatic cancer and molecular alterations in tumor pathogenesis, pancreatic cancer remains an oncologic challenge, with a 5-year survival rate of less than 5%. Pancreatic adenocarcinoma is arguably the most lethal of all cancers, with more than 95% of patients diagnosed with the disease dying from it, more than half within 6 months. In the United States, it ranks fourth among the leading causes of cancer death, accounting for more than 30 000 deaths annually (1). There is no effective therapy for pancreatic cancer other than early resection, but only a small percentage of patients are good candidates for surgery. Gemcitabine is the current conventional chemotherapy for pancreatic cancer, and it provides meager benefits (2). Combinations of gemcitabine with radiation or with other cytotoxic agents have also proven disappointing. Because of the poor response to these standard forms of therapy, recent efforts have focused on the application of novel, biologically targeted agents aimed at well-known cancer mechanisms. Examples of these approaches include compounds that target vascular endothelial growth factor receptors, e.g., bevacizumab; the epidermal growth factor receptor (EGFR), e.g., cetuximab; the EGFR-activating tyrosine kinase, e.g., erlotinib and gefitinib; and K-ras, e.g., farnesyol transferase inhibitor tipifarnib. However, most of the early clinical trials with the newer agents have shown no (2, 3) or only very modest (4) survival advantage compared with standard gemcitabine treatment. Clearly, new targets and therapeutic approaches are needed for this disease. Therapeutic target development requires identification of novel molecules, validation of their functional importance, understanding their mechanisms of action, and strategies for intervention. S100P has recently been found to be overexpressed in pancreatic (5–7), breast (8), and lung (9) cancers. S100P is a 95-amino acid member of the S100 family of proteins (10). S100P is functionally important for pancreatic cancer cell growth and survival, in that we previously observed that levels of cellular S100P affect the rate of tumor growth in vivo and resistance of pancreatic cancer cells against 5-fluorouracil treatment in vitro (11). In colon cancer cell lines, S100P levels are associated with resistance to chemotherapy (12). In lung cancer, S100P levels are associated with decreased patient survival (9). S100P is also associated with increased metastasis and decreased patient survival in breast cancer (8). Taken together, the evidence suggests that overexpressed S100P may increase tumor growth and metastasis and decrease patient survival. If so, blocking S100P function might improve responses to therapeutic treatments. The mechanisms of action of S100P have recently been elucidated in studies with pancreatic cancer cells. We found that S100P is secreted by pancreatic cancer cells and acts extracellularly through interactions with a cell surface protein receptor for advanced glycation end-products (RAGE) (13). RAGE is a multiligand receptor that interacts with a variety of molecules, including advanced glycation end-products, S100 molecules (S100B, S100A12, S100P), amyloid, and amphoterin (14). RAGE participates in a number of important pathologic processes, including Alzheimer’s disease, diabetes, inflammation, and cancer (14). Activation of RAGE by S100P stimulates several cellular signaling pathways, including the Mitogen-activated protein (MAP) kinase and nuclear factor-κ B (NFκB) pathways (13). NFκB signaling may be of particular importance because basal NFκB activity is elevated in the majority of pancreatic cancers (15) and elevated NFκB activity is associated with increased resistance to therapies (16, 17). Therefore, interventions that block the ability of S100P to activate RAGE may provide therapeutic benefit. In the current study, we focused on the effects of cromolyn (disodium 1,3-bis [(2 ′-carboxylatochromon-5 ′-yl)oxy]-2-hydroxypropane), an antiallergy compound (18) that has previously been shown to bind specifically to other members of the S100 protein family (S100A1, S100A12, S100A13) (19–21). We examined the interactions of cromolyn with S100P and its effects on S100P activation of RAGE. We then measured the consequences of these effects on cell proliferation, invasion, NFκB activity, and responses to gemcitabine using three pancreatic cancer cell lines BxPC-3 and MPanc-96 (which express endogenous S100P) and Panc-1 (which do not express S100P) and mouse models of pancreatic adenocarcinoma using these cell lines.

  • Cromolyn blocks S100P activation of RAGE, reduces pancreatic cancer growth and invasion and enhances gemcitabine chemotherapy
    Cancer Research, 2006
    Co-Authors: Thiruvengadam Arumugam, Vijaya Ramachandran, Craig D. Logsdon
    Abstract:

    Proc Amer Assoc Cancer Res, Volume 47, 2006 4625 Background: Pancreatic cancer remains an oncological challenge with a 5-year survival rate below 5%. Current therapies are unsatisfactory and patient outcome is dismal such that new treatments are desperately needed. Previously, we found that S100P is over expressed in more than 90% of pancreatic cancer, is secreted by cancer cells, activates the receptor for advanced glycation end-products (RAGE) and plays a major role in tumor growth and invasion (Clinical. Can. Res.2005 Aug 1;11(15):5356-64). Recent publications suggested that the anti-allergic drug cromolyn might interact with S100 molecules. Therefore, in the current study we sought to examine the ability of cromolyn to bind with S100P and inhibit its interactions with RAGE and its effects on pancreatic cancer. Methods: A cromolyn drug affinity column was used to determine the interaction between S100P and cromolyn. The ability of cromolyn to interfere with the interaction of S100P with its receptor RAGE was analyzed by co-immunoprecipitation studies. Cancer cell growth and invasion were analyzed with cells without endogenous S100P (Panc-1) and also cells with endogenous S100P (BxPc3 and Mpanc-96) in vitro and in vivo . In orthotopic tumor models, cromolyn (5mg/k.g.b.wt/daily by i.p.) was administered with and without gemcitabine (125mg/k.g.bt/twice a month) and tumor growth and invasion were monitored using bioluminescence imaging every week for six weeks. Results: S100P was retained by a cromolyn drug affinity column, indicating a direct interaction between these molecules. Cromolyn also blocked the interaction of S100P and RAGE in co-immunoprecipitation experiments. In vitro , cromolyn inhibited the growth and invasiveness of pancreatic cancer cells with endogenous S100P (BxPc3 and Mpanc-96), but not Panc-1 cells that lack endogenous S100P. In orthotopic tumor models, cromolyn treatment significantly reduced the growth and metastasis of tumors developed from S100P expressing cancer cells (BxPc3 and Mpanc-96) but not cancer cells lacking S100P (Panc-1). Cromolyn also enhanced the efficiency of gemcitabine and effects of the combination were greater than either drug alone. The combination resulted in a dramatic reduction in tumor growth (BxPc3 and Mpanc-96) and the almost complete absence of metastasis to liver and lung. Conclusion: Our findings suggest that cromolyn, through its ability to interfere with S100P activation of RAGE, inhibits pancreatic cancer growth and metastasis and increases the efficiency of chemotherapy. Thus, cromolyn treatments should be considered to enhance standard chemotherapy for pancreatic cancer.

  • S100P stimulates cell proliferation and survival via receptor for activated glycation end products rage
    Journal of Biological Chemistry, 2004
    Co-Authors: Thiruvengadam Arumugam, Diane M Simeone, Ann Marie Schmidt, Craig D. Logsdon
    Abstract:

    Abstract S100P is a member of the S100 protein family that is expressed in several malignant neoplasms. Currently the effects of this molecule on cell function are unknown. In the present study we investigated the biological effects and mechanisms of action of S100P using NIH3T3 cells. Expression of S100P in NIH3T3 cells led to the presence of S100P in the culture medium, increased cellular proliferation, and enhanced survival after detachment from the culture substrate or after exposure to the chemotherapeutic agent 5-flurouracil. The proliferation and survival effects of S100P expression were duplicated in a time- and concentration-dependent manner by the extracellular addition of purified S100P to wild-type NIH3T3 cells and correlated with the activation of extracellular-regulated kinases (Erks) and NF-κB. To determine the mechanisms involved in these effects, we tested the hypothesis that S100P activated RAGE (receptor for activated glycation end products). We found that S100P co-immunoprecipitated with RAGE. Furthermore, the effects of S100P on cell signaling, proliferation, and survival were blocked by agents that interfere with RAGE including administration of an amphoterin-derived peptide known to antagonize RAGE activation, anti-RAGE antibodies, and by expression of a dominant negative RAGE. These data suggest that S100P can act in an autocrine manner via RAGE to stimulate cell proliferation and survival.

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  • co expression co location of s100 proteins s100b s100a1 and s100a2 and protein kinase c pkc beta eta and zeta in a rat model of cerebral basilar artery vasospasm
    Neuropathology and Applied Neurobiology, 2005
    Co-Authors: Florence Lefranc, Christine Decaestecker, Claus W Heizmann, Robert Kiss, Jacques Brotchi, O Dewitte, Tatjana Mijatovic
    Abstract:

    OBJECT: The cellular events leading to cerebral vasospasm after subarachnoid haemorrhages (SAH) involve a number of members of the protein kinase C (PKC) family. However, whereas calcium is thought to play a number of major roles in the pathophysiology of SAH, a number of PKCs function independently of calcium. We recently emphasized the potential role of the calcium-binding S100 proteins in a 'double haemorrhage' rat model of SAH-induced vasospasm. A number of S100 proteins are known to interfere directly with PKC, or indirectly with PKC substrates. We therefore investigated whether specific S100 proteins and PKCs are co-expressed/co-located in a rat model of SAH-induced vasospasm. METHODS AND RESULTS: SAH-induced vasospasm in rats (by means of a double cisternal injection of autologous blood from a rat femoral artery) distinctly modified the expression levels of calcium-dependent PKC-alpha and PKC-beta and calcium-independent PKC-eta and PKC-zeta in endothelial and smooth-muscle cells. The RNA levels of these four PKC isotypes were determined by quantitative RT-PCR. The present study reveals that, in endothelial cells, the S100B expression/location correlate well with those of PKC-eta, and those of S100A1 with PKC-beta. In smooth-muscle cells S100A2 expression/location correlate with those of PKC-eta, and those of S100B with PKC-zeta. CONCLUSION: The present data argue in favour of a joint action of the S100 protein network and the PKC signalling pathway during cerebral vasospasm.

  • Structural Insight into Human Zn2+-Bound S100A2 from NMR and Homology Modeling
    Biochemical and biophysical research communications, 2001
    Co-Authors: Antonio Randazzo, Beat W Schafer, Claus W Heizmann, Christian Acklin, Walter J. Chazin
    Abstract:

    Abstract The S100 subfamily of EF-hand proteins is distinguished by the binding of Zn 2+ in addition to Ca 2+ . In an effort to understand the role of Zn 2+ in modulating the activity of S100 proteins, we have carried out heteronuclear NMR studies of Zn 2+ -bound S100A2 and obtained near complete resonance assignments. This analysis revealed an equilibrium between multiple isoforms due to cis-trans isomerism of proline residues in flexible regions of the protein. The secondary structure of S100A2 has been determined based on the NMR chemical shift index (CSI) technique. The protein is found to possess essentially the same secondary structure found in other S100 proteins such as S100A6 and S100B. Homology models have been built based on the high resolution three-dimensional structures of other S100 proteins. The models predict two Zn 2+ binding clusters, one involving residues His17-Cys21-Cys93 and the other Cys2-His39, and with Cys86 participating in either the N-terminal or the C-terminal binding site.

  • s100 proteins in corpora amylacea from normal human brain
    Brain Research, 2000
    Co-Authors: Daphne Hoyaux, Beat W Schafer, Christine Decaestecker, Isabelle Salmon, Thomas Vogl, Claus W Heizmann, Robert Kiss, Roland Pochet
    Abstract:

    Corpora amylacea (C.A.) also named polyglucosan bodies (P.B.) are one of the hallmarks of normal brain aging. Although their functions are not yet clear, C.A. increase in number in patients suffering from neurodegenerative diseases. C.A. contain 88% of hexoses and 4% of proteins. Most of the proteins in C.A. are aging or stress proteins such as heat shock proteins, ubiquitinated proteins and advanced glycation end products which are also proinflammatory products. Stimulated by the potential role played by some S100 proteins in the inflammatory process which may be triggered in C.A., we investigated, by immunohistochemistry, the presence of different S100 proteins (S100A1, S100A2, S100A3, S100A4, S100A5, S100A6, S100A8, S100A9, S100A12 and S100B) in C.A. from normal human brain. Among the ten S100 proteins analyzed, nine (S100A) were detected in C.A. Three S100 proteins (S100A8, S100A9, S100A12) which are highly expressed in activated macrophages and used as inflammatory markers were detected in C.A. S100A8 was, in addition, found in thick neuronal processes from the pons. One (S100B) could not be found in C.A. although it was highly expressed in astrocytes. In C.A., the staining intensity was estimated by computer-assisted microscopy and gave the following order: S100A1 congruent withS100A8 congruent with S100A9>S100A5> or =S100A4>S100A12>S100A6> S100A2=S100A3. The potential inflammatory role played by S100 proteins in C.A. is discussed.

  • expression pattern of s100 calcium binding proteins in human tumors
    International Journal of Cancer, 1996
    Co-Authors: Beat W Schafer, Claus W Heizmann
    Abstract:

    The S100 Ca2+-binding proteins recently became of major interest because of their differential expression in neoplastic tissues, their involvement in metastatic processes, and the clustered organization of at least 10 S100 genes on human chromosome 1q21, a region frequently rearranged in several tumors. As a first attempt towards a specific and differentiated immunohistochemical classification of human tumors, we produced, purified and characterized a number of human recombinant S100 proteins and raised specific polyclonal antibodies. Their distinct cellular and intracellular localization was examined by immunohistochemical methods in normal and cancerogenic human tissues and cell lines. S100A1 and S100A2 can be detected in a few normal tissues only, whereas S100A4, S100A6, and S100B are expressed at higher levels in cancer tissues. In the future, these S100 antibodies will potentially be of great value in cancer diagnosis and therapy. © 1996 Wiley-Liss, Inc.

  • isolation of a yac clone covering a cluster of nine s100 genes on human chromosome 1q21 rationale for a new nomenclature of the s100 calcium binding protein family
    Genomics, 1995
    Co-Authors: Beat W Schafer, Roland Wicki, Dieter Engelkamp, Mariegenevieve Mattei, Claus W Heizmann
    Abstract:

    S100 proteins are low-molecular-weight calcium-binding proteins of the EF- hand superfamily and appear to be involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. More than 10 members of the S100 protein family have been described from human sources so far. We have now isolated a YAC clone from human chromosome 1q21, on which 9 different genes coding for S100 calcium-binding proteins could be localized. Moreover, we have mapped the gene coding for S100P to human chromosome 4p16 and thereby completed the chromosomal assignments of all known human S100 genes. The clustered organization of S100 genes in the 1q21 region allows us to introduce a new logical nomenclature for these genes, which is based on the physical arrangement on the chromosomes. The new nomenclature should facilitate the further the understanding of this protein family and be easily expandable to other species. 31 refs., 4 figs., 1 tab.

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