Anoikis

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Aaron D. Schimmer - One of the best experts on this subject based on the ideXlab platform.

  • A genome wide shRNA screen identifies α/β hydrolase domain containing 4 (ABHD4) as a novel regulator of Anoikis resistance
    Apoptosis, 2012
    Co-Authors: Craig D. Simpson, Rose Hurren, Dahlia Kasimer, Neil Maclean, Yanina Eberhard, Troy Ketela, Jason Moffat, Aaron D. Schimmer
    Abstract:

    Acquisition of resistance to anchorage dependant cell death, a process termed Anoikis, is a requirement for cancer cell metastasis. However, the molecular determinants of Anoikis resistance and sensitivity are poorly understood. To better understand resistance to Anoikis we conducted a genome wide lentiviral shRNA screen to identify genes whose knockdown render Anoikis-sensitive RWPE-1 prostate cells resistant to Anoikis. RWPE-1 cells were infected with a pooled lentiviral shRNA library with 54,021 shRNA targeting 11,255 genes. After infection, an Anoikis-resistant cell population was selected and shRNA sequences were amplified and sequenced. Thirty-four shRNA sequences reproducibly protected RWPE-1 cells from Anoikis after culture under suspension conditions including the top validated hit, α/β hydrolase domain containing 4 (ABHD4). In validation studies, ABHD4 knockdown inhibited Anoikis in RWPE-1 cells as well as Anoikis sensitive NP69 nasopharyngeal and OVCAR3 ovarian cancer cells, while over-expression of the gene increased sensitivity. Induction of Anoikis after ABHD4 knockdown was associated with cleavage of PARP and activation of caspases-3, but was independent in changes of FLIP, FAK and Src expression. Interestingly, induction of Anoikis after ABHD4 knockdown was independent of the known role of ABHD4 in the anandamide synthesis pathway and the generation of glycerophospho- N -acyl ethanolamines. Thus, ABHD4 is a novel genetic regulator of Anoikis sensitivity.

  • Anoikis resistance and tumor metastasis
    Cancer Letters, 2008
    Co-Authors: Craig D. Simpson, Kika Anyiwe, Aaron D. Schimmer
    Abstract:

    As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed "Anoikis". Tumour cells that acquire malignant potential have developed mechanisms to resist Anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to Anoikis. Likewise, roadblocks in the mitochondrial pathway, such as over-expression of the Bcl-2 family of anti-apoptotic proteins, can also confer resistance to Anoikis. This review will focus on the roles of the death receptor and mitochondrial pathways in Anoikis and Anoikis resistance and how targeting defects in these pathways can restore sensitivity to Anoikis and serve as the basis for therapeutic adjuncts that prevent metastasis.

  • A chemical screen identifies anisomycin as an Anoikis sensitizer that functions by decreasing FLIP protein synthesis.
    Cancer Research, 2007
    Co-Authors: Imtiaz A. Mawji, Craig D. Simpson, Marcela Gronda, Moyo A. Williams, Rose Hurren, Clare Henderson, Alessandro Datti, Jeffrey L. Wrana, Aaron D. Schimmer
    Abstract:

    Malignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed “Anoikis.” Resistance to Anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of Anoikis, we designed, automated, and conducted a high-throughput chemical screen for Anoikis sensitizers. PPC-1 Anoikis–resistant prostate cancer cells were seeded in hydrogel-coated ultralow binding plates for suspension conditions and standard tissue culture plates to promote adhesion. After seeding, cells were treated with aliquots from a library of previously characterized small molecules, and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, assay. From this chemical screen, we identified anisomycin that induced apoptosis in suspension conditions, but was not toxic to these cells grown under adherent conditions. Anisomycin sensitized cells to Anoikis by decreasing levels of the caspase-8 inhibitor FLIP and subsequently activating the death receptor pathway of caspase activation. Although anisomycin activated c-Jun-NH2-kinase and p38, these kinases were not functionally important for the effect of anisomycin on Anoikis and FLIP. Rather, anisomycin decreased FLIP and sensitized cells to Anoikis by inhibiting its protein synthesis. Finally, we showed that anisomycin decreased distal tumor formation in a mouse model of prostate cancer metastases. Thus, a novel chemical screen identified anisomycin as an Anoikis sensitizer that acts by decreasing FLIP protein synthesis. Our results suggest that FLIP is a suppressor of Anoikis and inhibiting FLIP protein synthesis may be a useful antimetastatic strategy. [Cancer Res 2007;67(17):8307–15]

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

  • A genome wide shRNA screen identifies α/β hydrolase domain containing 4 (ABHD4) as a novel regulator of Anoikis resistance
    Apoptosis, 2012
    Co-Authors: Craig D. Simpson, Rose Hurren, Dahlia Kasimer, Neil Maclean, Yanina Eberhard, Troy Ketela, Jason Moffat, Aaron D. Schimmer
    Abstract:

    Acquisition of resistance to anchorage dependant cell death, a process termed Anoikis, is a requirement for cancer cell metastasis. However, the molecular determinants of Anoikis resistance and sensitivity are poorly understood. To better understand resistance to Anoikis we conducted a genome wide lentiviral shRNA screen to identify genes whose knockdown render Anoikis-sensitive RWPE-1 prostate cells resistant to Anoikis. RWPE-1 cells were infected with a pooled lentiviral shRNA library with 54,021 shRNA targeting 11,255 genes. After infection, an Anoikis-resistant cell population was selected and shRNA sequences were amplified and sequenced. Thirty-four shRNA sequences reproducibly protected RWPE-1 cells from Anoikis after culture under suspension conditions including the top validated hit, α/β hydrolase domain containing 4 (ABHD4). In validation studies, ABHD4 knockdown inhibited Anoikis in RWPE-1 cells as well as Anoikis sensitive NP69 nasopharyngeal and OVCAR3 ovarian cancer cells, while over-expression of the gene increased sensitivity. Induction of Anoikis after ABHD4 knockdown was associated with cleavage of PARP and activation of caspases-3, but was independent in changes of FLIP, FAK and Src expression. Interestingly, induction of Anoikis after ABHD4 knockdown was independent of the known role of ABHD4 in the anandamide synthesis pathway and the generation of glycerophospho- N -acyl ethanolamines. Thus, ABHD4 is a novel genetic regulator of Anoikis sensitivity.

  • inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to Anoikis and prevents distant tumor formation
    Cancer Research, 2009
    Co-Authors: Craig D. Simpson, Kika Anyiwe, Imtiaz A. Mawji, Marcela Gronda, Moyo A. Williams, Rose Hurren, Xiaoming Wang, Amudha Venugopal, Sonia Cheng, Stefano Serra
    Abstract:

    Normal epithelial cells undergo apoptosis upon detachment from the extracellular matrix, a process termed "Anoikis." However, malignant epithelial cells with metastatic potential resist Anoikis and can survive in an anchorage-independent fashion. Molecules that sensitize resistant cells to Anoikis will be useful chemical probes to understand this pathway. To identify novel Anoikis sensitizers in Anoikis-resistant PPC-1 prostate adenocarcinoma cells, a library of 2,000 off-patent drugs and natural products was screened for their ability to preferentially induce cell death in suspension over adherent culture conditions. This screen identified five members of the family of cardiac glycosides as Anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin. We conducted further studies with ouabain to discern the mechanism of cardiac glycoside-induced Anoikis sensitization. Ouabain initiated Anoikis through the mitochondrial pathway of caspase activation. In addition, ouabain sensitized cells to Anoikis by inhibiting its known target, the Na(+)/K(+) ATPase pump, and inducing hypoosmotic stress. Resistance to Anoikis permits cancer cells to survive in the circulation and facilitates their metastasis to distant organs, so we tested the effects of Na(+)/K(+) ATPase inhibition on distant tumor formation in mouse models. In these mouse models, ouabain inhibited tumor metastases but did not alter the growth of subcutaneous tumors. Thus, we have identified a novel mechanism to sensitize resistant cells to Anoikis and decrease tumor metastasis. These results suggest a potential mechanism for the observed clinical reduction in metastasis and relapse in breast cancer patients who have undergone treatments with cardiac glycosides.

  • Anoikis resistance and tumor metastasis
    Cancer Letters, 2008
    Co-Authors: Craig D. Simpson, Kika Anyiwe, Aaron D. Schimmer
    Abstract:

    As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed "Anoikis". Tumour cells that acquire malignant potential have developed mechanisms to resist Anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to Anoikis. Likewise, roadblocks in the mitochondrial pathway, such as over-expression of the Bcl-2 family of anti-apoptotic proteins, can also confer resistance to Anoikis. This review will focus on the roles of the death receptor and mitochondrial pathways in Anoikis and Anoikis resistance and how targeting defects in these pathways can restore sensitivity to Anoikis and serve as the basis for therapeutic adjuncts that prevent metastasis.

  • A chemical screen identifies anisomycin as an Anoikis sensitizer that functions by decreasing FLIP protein synthesis.
    Cancer Research, 2007
    Co-Authors: Imtiaz A. Mawji, Craig D. Simpson, Marcela Gronda, Moyo A. Williams, Rose Hurren, Clare Henderson, Alessandro Datti, Jeffrey L. Wrana, Aaron D. Schimmer
    Abstract:

    Malignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed “Anoikis.” Resistance to Anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of Anoikis, we designed, automated, and conducted a high-throughput chemical screen for Anoikis sensitizers. PPC-1 Anoikis–resistant prostate cancer cells were seeded in hydrogel-coated ultralow binding plates for suspension conditions and standard tissue culture plates to promote adhesion. After seeding, cells were treated with aliquots from a library of previously characterized small molecules, and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, assay. From this chemical screen, we identified anisomycin that induced apoptosis in suspension conditions, but was not toxic to these cells grown under adherent conditions. Anisomycin sensitized cells to Anoikis by decreasing levels of the caspase-8 inhibitor FLIP and subsequently activating the death receptor pathway of caspase activation. Although anisomycin activated c-Jun-NH2-kinase and p38, these kinases were not functionally important for the effect of anisomycin on Anoikis and FLIP. Rather, anisomycin decreased FLIP and sensitized cells to Anoikis by inhibiting its protein synthesis. Finally, we showed that anisomycin decreased distal tumor formation in a mouse model of prostate cancer metastases. Thus, a novel chemical screen identified anisomycin as an Anoikis sensitizer that acts by decreasing FLIP protein synthesis. Our results suggest that FLIP is a suppressor of Anoikis and inhibiting FLIP protein synthesis may be a useful antimetastatic strategy. [Cancer Res 2007;67(17):8307–15]

Sanjay K. Srivastava - One of the best experts on this subject based on the ideXlab platform.

  • HER2-mediated GLI2 stabilization promotes Anoikis resistance and metastasis of breast cancer cells.
    Cancer letters, 2018
    Co-Authors: Parul Gupta, Neel M. Fofaria, Nehal Gupta, Alok Ranjan, Sanjay K. Srivastava
    Abstract:

    Breast cancer metastasis is a multi-step process and requires cells to overcome Anoikis. Anoikis is defined as cell-death that occurs due to loss of cell adhesion. During the course of cancer progression, tumor cells acquire resistance to Anoikis. However, mechanisms of Anoikis resistance are not clear. Human epidermal growth receptor 2 (HER2) overexpressing breast tumors are known to be highly aggressive and metastatic. The mechanisms correlating HER2 with metastasis are poorly understood. We observed increased Anoikis resistance in HER2 overexpressing breast cancer cells. In addition, we identified that HER2 overexpression was also associated with increased sonic hedgehog (SHH) signaling especially GLI2, and that inhibition of SHH pathway suppressed Anoikis resistance. GSK3β is known to facilitate proteasome-mediated degradation of GLI2. Moreover, we observed that silencing of GLI2 resulted in reduced migration and invasion of HER2 overexpressing cells. Anoikis resistant HER2 overexpressing cells also showed increased rate and extent of metastasis in vivo, as compared to wild type Anoikis resistant cells. Taken together, this study indicates a novel role of HER2/GSK3β/GLI2 axis in Anoikis resistance and metastasis, and that GLI2 could be a potential target for anti-cancer therapies.

  • STAT3 induces Anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.
    Carcinogenesis, 2014
    Co-Authors: Neel M. Fofaria, Sanjay K. Srivastava
    Abstract:

    Tumor cells need to attain Anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The mechanism by which pancreatic cancer cells resist Anoikis and metastasize is not well established. Significant proportion of pancreatic cancer cells resisted Anoikis when grown under anchorage-independent conditions. The cells that resisted Anoikis showed higher migratory and invasive characteristics than the cells that were cultured under anchorage-dependent condition. Interestingly, Anoikis-resistant cells exhibited significantly increased expression and phosphorylation of signal transducer and activation of transcription 3 (STAT3) at Tyr 705, as compared to adherent cells. AG 490 and piplartine (PL) induced significant Anoikis in Anoikis-resistant pancreatic cancer cells. Silencing STAT3 not only reduced the capacity of pancreatic cancer cells to resist Anoikis but also reversed its invasive characteristics. Interleukin-6 treatment and overexpression of STAT3 enhanced Anoikis resistance and protected the cells from PL-induced Anoikis. PL-treated cells completely failed to develop tumors when injected subcutaneously in immune-compromised mice. Moreover, these cells also failed to metastasize when injected intravenously. On the other hand, untreated Anoikis-resistant cells not only formed aggressive tumors but also metastasized substantially to lungs and liver when injected intravenously. Metastatic nodules formed by untreated Anoikis-resistant cells in lungs exhibited significant phosphorylation of STAT3 at Tyr705. Taken together, our results established the critical involvement of STAT3 in conferring Anoikis resistance to pancreatic cancer cells and increased metastasis.

  • Critical role of STAT3 in melanoma metastasis through Anoikis resistance
    Oncotarget, 2014
    Co-Authors: Neel M. Fofaria, Sanjay K. Srivastava
    Abstract:

    Anoikis is an anchorage-independent cell death. Resistance to Anoikis is one of the key features of metastatic cells. Here, we analyzed the role of STAT3 in Anoikis resistance in melanoma cells leading to metastasis. When grown under anchorage-independent conditions, significant proportion of cells resisted Anoikis and these resistant cells had higher rate of migration and invasion as compared to the cells grown under anchorage-dependent conditions. The Anoikis resistant cells also had significantly higher expression and phosphorylation of STAT3 at Y705 than the cells that were attached to the basement membrane. STAT3 inhibitors, AG 490 and piplartine (PL) induced Anoikis in a concentration-dependent manner in Anoikis resistant cells. Over-expression of STAT3 or treatment with IL-6 not only increased Anoikis resistance, but also protected the cancer cells from PL-induced Anoikis. On the other hand, silencing STAT3 decreased the potential of cancer cells to resist Anoikis and to migrate. STAT3 knock-down cells and PL treated cells did not form tumors as well as failed to metastasize in SCID-NSG mice as compared to untreated anchorage-independent cells, which formed big tumors and extensively metastasized. In summary, our results for the first time establish STAT3 as a critical player that renders Anoikis resistance to melanoma cells and enhance their metastatic potential.

  • diindolylmethane mediated gli1 protein suppression induces Anoikis in ovarian cancer cells in vitro and blocks tumor formation ability in vivo
    Journal of Biological Chemistry, 2012
    Co-Authors: Prabodh K. Kandala, Sanjay K. Srivastava
    Abstract:

    Anoikis is a cell death that occurs due to detachment of a cell from the extracellular matrix (ECM). Resistance to Anoikis is a primary feature of a cell that undergoes metastasis. In this study for the first time, we demonstrated the potential role of Gli1 in Anoikis resistance. Treatment of various ovarian cancer cells by different concentrations of diindolylmethane (DIM), an active ingredient of cruciferous vegetables, reduced the Anoikis resistance in a concentration-dependent manner. Reduction in Anoikis resistance was associated with a decrease in the expression of Gli1 and an increase in the cleavage of poly(ADP-ribose) polymerase (PARP). Sonic hedgehog (Shh) treatment not only increased the expression of Gli1, but also blocked Anoikis induced by DIM and abrogated the change in the expression of Gli1 and cleaved PARP by DIM. To confirm the role of Gli1, hedgehog inhibitor cyclopamine, Gli1 siRNA and Gli1−/− mouse embryonic fibroblasts (MEFs) were used. Cyclopamine treatment alone significantly reduced Anoikis resistance in A2780 and OVCAR-429 cells. Cyclopamine-mediated reduction in Anoikis resistance was associated with reduced expression of Gli1 and induction of cleaved PARP. Shh treatment blocked cyclopamine-induced Anoikis. Silencing Gli1 expression induced Anoikis and cleavage of PARP in A2780 and OVCAR-429 cells. Furthermore, Gli1−/− MEFs were more sensitive to Anoikis compared with Gli1+/+ MEFs. Our in vivo studies established that DIM- or cyclopamine-treated ovarian cancer cells under suspension culture conditions drastically lost their ability of tumor formation in vivo in mice. Taken together, our results establish that Gli1 is a critical player in Anoikis resistance in ovarian cancer.

  • Diindolylmethane-mediated Gli1 Protein Suppression Induces Anoikis in Ovarian Cancer Cells in Vitro and Blocks
    2012
    Co-Authors: Prabodh K. Kandala, Sanjay K. Srivastava
    Abstract:

    Anoikis is a cell death that occurs due to detachment of a cell from the extracellular matrix (ECM). Resistance to Anoikis is a primary feature of a cell that undergoes metastasis. In this study for the first time, we demonstrated the potential role of Gli1 in Anoikis resistance. Treatment of various ovarian cancer cells by different concentrations of diindolylmethane (DIM), an active ingredient of cruciferous vegetables, reduced the Anoikis resistance in a concentration-dependent manner. Reduction in Anoikis resistance was associated with a decrease in the expression of Gli1 and an increase in the cleavage of poly(ADP-ribose) polymerase (PARP). Sonic hedgehog (Shh) treatment not only increased the expression of Gli1, but also blocked Anoikis induced by DIM and abrogated the change in the expression of Gli1 and cleaved PARP by DIM. To confirm the role of Gli1, hedgehog inhibitor cyclopamine, Gli1 siRNA and Gli1 / mouse embryonic fibroblasts (MEFs) were used. Cyclopamine treatment alone significantly reduced Anoikis resistance in A2780 and OVCAR-429 cells. Cyclopamine-mediated reduction in Anoikis resistance was associated with reduced expression of Gli1 and induction of cleaved PARP. Shh treatment blocked cyclopamine-induced Anoikis. Silencing Gli1 expression induced Anoikis and cleavage of PARP in A2780 and OVCAR-429 cells. Furthermore, Gli1 / MEFs were more sensitive to Anoikis compared with Gli1 / MEFs. Our in vivo studies established that DIM- or cyclopamine-treated ovarian cancer cells under suspension culture conditions drastically lost their ability of tumor formation in vivo in mice. Taken together, our results establish that Gli1 is a critical player in Anoikis resistance in ovarian cancer.

Yvonne L. Kapila - One of the best experts on this subject based on the ideXlab platform.

  • Shedding of NG2 by MMP-13 Attenuates Anoikis
    DNA and cell biology, 2014
    Co-Authors: Nam Eok Joo, Di Miao, Mercedes Bermúdez, William B. Stallcup, Yvonne L. Kapila
    Abstract:

    Disruption of cell–matrix interactions can lead to Anoikis—apoptosis due to loss of matrix contacts. We previously showed that Nerve/glial antigen 2 (NG2) is a novel Anoikis receptor. Specifically, overexpression of NG2 leads to Anoikis propagation, whereas its suppression leads to Anoikis attenuation. Interestingly, NG2 expression decreases in late Anoikis, suggesting that NG2 reduction is also critical to this process. Thus, we hypothesized that NG2 undergoes cleavage to curtail Anoikis propagation. Further, since matrix metalloproteinases (MMPs) cleave cell surface receptors, play a major role in modulating apoptosis, and are associated with death receptor cleavage during apoptosis, we further hypothesized that cleavage of NG2 could be mediated by MMPs to regulate Anoikis. Indeed, Anoikis conditions triggered release of the NG2 extracellular domain into condition media during late apoptosis, and this coincided with increased MMP-13 expression. Treatment with an MMP-13 inhibitor and MMP-13 siRNA increas...

  • Receptor-interacting protein (RIP) and Sirtuin-3 (SIRT3) are on opposite sides of Anoikis and tumorigenesis.
    Cancer, 2012
    Co-Authors: Pachiyappan Kamarajan, Eric Verdin, Turki Y. Alhazzazi, Yvonne L. Kapila, Theodora E. Danciu, Nisha J. D'silva
    Abstract:

    BACKGROUND: Regulating cross-talk between Anoikis and survival signaling pathways is crucial to regulating tissue processes and mitigating diseases like cancer. Previously, the authors demonstrated that Anoikis activates a signaling pathway involving the CD95/ Fas-mediated signaling pathway that is regulated by receptor-interacting protein (RIP), a kinase that shuttles between Fas-mediated cell death and integrin/focal adhesion kinase (FAK)-mediated survival pathways. Because it is known that sirtuin-3 (SIRT3), a nicotinamide adenine dinucleotide-dependent deacetylase, regulates cell survival, metabolism, and tumorigenesis, the authors hypothesized that SIRT3 may engage in cross-talk with Fas/RIP/integrin/FAK survival-death pathways in cancer cell systems. METHODS: Using immunohistochemical staining, immunoblotting, human tissue microarrays, and overexpression and suppression approaches in vitro and in vivo, the roles of RIP and SIRT3 were examined in oral squamous cell carcinoma (OSCC) Anoikis resistance and tumorigenesis. RESULTS: RIP and SIRT3 had opposite expression profiles in OSCC cells and tissues. Stable suppression of RIP enhanced SIRT3 levels, whereas stable suppression of SIRT3 did not impact RIP levels in OSCC cells. The authors observed that, as OSCC cells became Anoikis-resistant, they formed multicellular aggregates or oraspheres in suspension conditions, and their expression of SIRT3 increased as their RIP expression decreased. Also, Anoikis-resistant OSCC cells with higher SIRT3 and low RIP expression induced an increased tumor burden and incidence in mice, unlike their adherent OSCC cell counterparts. Furthermore, stable suppression of SIRT3 inhibited Anoikis resistance and reduced tumor incidence. CONCLUSIONS: The current results indicted that RIP is a likely upstream, negative regulator of SIRT3 in Anoikis resistance, and an Anoikis-resistant orasphere phenotype defined by higher SIRT3 and low RIP expression contributes to a more aggressive phenotype in OSCC development. Cancer 2012;118:5800-10. V C 2012 American Cancer Society.

  • Anoikis mediators in oral squamous cell carcinoma.
    Oral diseases, 2010
    Co-Authors: Julius Bunek, Pachiyappan Kamarajan, Yvonne L. Kapila
    Abstract:

    Anoikis - apoptotic cell death triggered by loss of extracellular matrix (ECM) contacts - is dysregulated in many chronic debilitating and fatal diseases. Mechanisms rendering tumor cells resistant to Anoikis, although not completely understood, possess significant therapeutic promise. In death receptor-mediated Anoikis mechanisms, focal adhesion kinase (FAK) and receptor-interacting protein (RIP) dissociate, leading to association of RIP with Fas, formation of the death-inducing signaling complex (DISC), activation of caspase-3, and propagation of Anoikis. In contrast, Anoikis resistance is accomplished through constitutive activation of survival pathways that include integrin-dependent activation of FAK and extracellular-signal-regulated kinase (ERK). In addition, FAK and RIP association confers Anoikis resistance by inhibiting the association of RIP with Fas and formation of the death signaling complex, which allows cells to escape Anoikis. Up-regulation of CD44 also contributes to survival signals and promotes Anoikis resistance. This review will focus on the roles of death receptors, prosurvival pathways, and the molecular players involved in Anoikis escalation and resistance in oral squamous cell carcinoma.

  • Anoikis triggers Mdm2-dependent p53 degradation.
    Molecular and Cellular Biochemistry, 2010
    Co-Authors: Abhijit Ghosh, Tina Chunyuan Chen, Yvonne L. Kapila
    Abstract:

    The extracellular matrix (ECM) plays a key role in cell–cell communication and signaling, and the signals it propagates are important for tissue remodeling and survival. However, signals from disease-altered ECM may lead to Anoikis—apoptotic cell death triggered by loss of ECM contacts. Previously, we found that an altered fibronectin matrix triggers Anoikis in human primary ligament cells via a pathway that requires p53 transcriptional downregulation. Here we show that this p53 reduction is suppressed by transfecting cells with Mdm2 antisense oligonucleotides or small interfering RNA. Similar results were found in cells treated to prevent p53 and Mdm2 interactions. When p53 was overexpressed in cells lacking Mdm2 and p53, p53 levels were unaffected by Anoikis conditions. However, cells cotransfected with p53 and wild type Mdm2, but not a mutant Mdm2, exhibited decreased p53 levels in response to Anoikis conditions. Thus, cells under Anoikis conditions undergo p53 degradation that is mediated by Mdm2.

Natasha Kyprianou - One of the best experts on this subject based on the ideXlab platform.

  • Anoikis and EMT: Lethal "Liaisons" during Cancer Progression.
    Critical reviews in oncogenesis, 2016
    Co-Authors: Zheng Cao, Theodore Livas, Natasha Kyprianou
    Abstract:

    Anoikis is a unique mode of apoptotic cell death that occurs consequentially to insufficient cell-matrix interactions. Resistance to Anoikis is a critical contributor to tumor invasion and metastasis. The phenomenon is regulated by integrins, which upon engagement with components of the extracellular matrix (ECM) form adhesion complexes and the actin cytoskeleton drives the formation of cell protrusions used to adhere to ECM, directing cell migration. The epithelial-mesenchymal transition (EMT) confers stem cell properties and leads to acquisition of a migratory and invasive phenotype by causing adherens junction breakdown and circumventing Anoikis in the tumor microenvironment. The investigation of drug discovery platforms for apoptosis-driven therapeutics identified several novel agents with antitumor action via reversing resistance to Anoikis, inhibiting survival pathways and impacting the EMT landscape in human cancer. In this review, we discuss current evidence on the contribution of the Anoikis phenomenon functionally linked to EMT to cancer metastasis and the therapeutic value of antitumor drugs that selectively reverse Anoikis resistance and/or EMT to impair tumor progression toward the development/optimization of apoptosis-driven therapeutic targeting of metastatic disease.

  • Targeting Anoikis resistance in prostate cancer metastasis.
    Molecular aspects of medicine, 2010
    Co-Authors: Shinichi Sakamoto, Natasha Kyprianou
    Abstract:

    Anoikis is a mode of apoptotic cell death, consequential to insufficient cell-matrix interactions and a critical player in tumor angiogenesis and metastasis. The events involved in tumor cell progression toward metastasis potential are mediated by integrins, which upon engagement with components of the extracellular matrix (ECM), reorganize to form adhesion complexes. Targeting apoptotic players is of immense therapeutic significance since resistance to apoptosis is not only critical in conferring therapeutic failure to standard treatment strategies, but Anoikis (apoptosis upon loss of anchorage and detachment from ECM) also plays an important role in angiogenesis and metastasis. The ability to survive in the absence of adhesion to the ECM, enables tumor cells to disseminate from the primary tumor site, invade a distant site and establish a metastatic lesion. Tumor cells can escape from detachment-induced apoptosis by controlling Anoikis pathways, including the extrinsic death receptor pathway and the ECM-integrin mediated cell survival pathway. Considering the functional promiscuity of individual signaling effectors, it is critical to dissect the molecular networks mechanistically driving tumor cells to evade Anoikis and embark on a metastatic spread. Resistance to die via Anoikis dictates tumor cell survival and provides a molecular basis for therapeutic targeting of metastatic prostate cancer. Further dissection of critical Anoikis signaling events will enable the therapeutic optimization of Anoikis targeting to impair prostate cancer metastasis prior to its initiation. This review will discuss the molecular understanding of Anoikis regulation in the tumor microenvironment and the in vivo pharmacological implementation of a novel class of antitumor-drugs to optimize apoptotic-based therapeutic targeting, bypassing Anoikis-resistance to impair prostate cancer progression to metastasis. Potential combination strategies targeting tumor vascularity (via Anoikis) and impairing tumor initiation (via "classic" apoptosis), provide strong therapeutic promise for metastatic prostate cancer by preventing the onset of metastasis.