The Experts below are selected from a list of 156 Experts worldwide ranked by ideXlab platform
Andrew S. Kraft - One of the best experts on this subject based on the ideXlab platform.
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Abstract LB-487: Pim Protein kinase inhibitors induce the unfolded Protein response and sensitize prostate cancer cells to killing by ABT-737-mediated apoptosis
Molecular and Cellular Biology, 2012Co-Authors: Jin H. Song, Andrew S. KraftAbstract:Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet anticancer efficacy of Pim kinase inhibitors on prostate cancer is unknown. We demonstrate for the first time that a genetically engineered decrease in Pim kinase levels or the addition of Pim kinase small molecule inhibitors (e.g. SMI-4a) to human prostate cancer cells, including LNCaP and PC-3, causes ER stress and activates the unfolded Protein response (UPR) stimulating increases in eIF-2α phosphorylation, ATF-4, CHOP Proteins, and cleavage of XBP-1. Because (1) Bcl-2 family Proteins reside on the ER lumen and play an important role in regulation of XBP-1 splicing, (2) Bcl-2 family members are over expressed in prostate cancer to enhance Pim kinase anti-cancer activity, and (3) Pim kinase inhibitors decrease Mcl-1 and increase Noxa Protein, we treated prostate cancer cell lines with SMI-4a plus the Bcl-2 family antagonist ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′-cap dependent translation and decreasing Protein half life. Additionally, Pim inhibition transcriptionally increased levels of the BH3 Protein Noxa by activating the UPR, lead to eIF2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 Protein activity. Notably, these specific Protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 Protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. We find that the Pim kinase inhibitors and ABT-737 are highly synergistic in killing prostate cancer both in vitro and when used together in a subcutaneous animal model of prostate cancer therapy. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-487. doi:1538-7445.AM2012-LB-487
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Abstract C14: Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737
Cancer Research, 2012Co-Authors: Jin H. Song, Andrew S. KraftAbstract:Abstract Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet Pim kinase inhibitors appear to have only limited effects on prostate cancer cell survival. Since overexpression of Bcl-2 family members are implicated in chemotherapeutic resistance in prostate cancer, we investigated the cooperative effects of Pim kinase inhibition with ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′- cap dependent translation and decreasing Protein half life. Additionally, Pim inhibition transcriptionally increased levels of the BH3 Protein Noxa by activating the unfolded Protein response (UPR), lead to eIF-2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 Protein activity. Notably, these specific Protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 Protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies. Citation Format: Jin H. Song, Andrew S. Kraft. Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C14.
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Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737
Cancer research, 2011Co-Authors: Jin H. Song, Andrew S. KraftAbstract:Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet Pim kinase inhibitors seem to have only limited effects on prostate cancer cell survival. Because overexpression of Bcl-2 family members are implicated in chemotherapeutic resistance in prostate cancer, we investigated the cooperative effects of Pim kinase inhibition with ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′-cap dependent translation and decreasing Protein half life. In addition, Pim inhibition transcriptionally increased levels of the BH3 Protein Noxa by activating the unfolded Protein response (UPR), lead to eIF-2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 Protein activity. Notably, these specific Protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 Protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies. Cancer Res; 72(1); 294–303. ©2011 AACR.
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novel benzylidene thiazolidine 2 4 diones inhibit pim Protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells
Molecular Cancer Therapeutics, 2009Co-Authors: Zanna Beharry, Marina Zemskova, Sandeep Mahajan, Fengxue Zhang, Zuping Xia, Michael B Lilly, Charles D Smith, Andrew S. KraftAbstract:The Pim Protein kinases play important roles in cancer development and progression, including prostate tumors and hematologic malignancies. To investigate the potential role of these enzymes as anticancer drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function as potent Pim Protein kinase inhibitors. With IC50 values in the nanomolar range, these compounds block the ability of Pim to phosphorylate peptides and Proteins in vitro and, when added to DU145 prostate cancer cells overexpressing Pim, inhibit the ability of this enzyme to phosphorylate a known substrate, the BH3 Protein BAD. When added to prostate cancer cell lines, including PC3, DU145, and CWR22Rv1, and human leukemic cells, MV4;11, K562, and U937 cells, these compounds induce G1-S cell cycle arrest and block the antiapoptotic effect of the Pim Protein kinase. The cell cycle arrest induced by these compounds is associated with an inhibition of cyclin-dependent kinase 2 and activity and translocation of the Pim-1 substrate p27Kip1, a cyclin-dependent kinase 2 inhibitory Protein, to the nucleus. Furthermore, when added to leukemic cells, these compounds synergize with the mammalian target of rapamycin inhibitor rapamycin to decrease the phosphorylation level of the translational repressor 4E-BP1 at sites phosphorylated by mammalian target of rapamycin. Combinations of rapamycin and the benzylidene-thiazolidine-2,4-diones synergistically block the growth of leukemic cells. Thus, these agents represent novel Pim inhibitors and point to an important role for the Pim Protein kinases in cell cycle control in multiple types of cancer cells. [Mol Cancer Ther 2009;8(6):1473–83]
Massimo Crimi - One of the best experts on this subject based on the ideXlab platform.
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Plants expressing murine pro-apoptotic Protein Bid do not have enhanced PCD
BMC research notes, 2020Co-Authors: Anna Manara, Zahra Imanifard, Linda Fracasso, Diana Bellin, Massimo CrimiAbstract:The purpose of this study was to explore whether plant programmed cell death (PCD) cascade can sense the presence of the animal-only BH3 Protein Bid, a BCL-2 family Protein known to play a regulatory role in the signaling cascade of animal apoptosis. We have expressed the mouse pro-apoptotic Protein Bid in Arabidopsis thaliana and in Nicotiana tabacum. We did not obtain any transformed plant constitutively expressing the truncated Protein (tBid—i.e. the caspase-activated form) whereas ectopic expression of the full-length Protein (flBid) does not interfere with growth and development of the transformed plants. To verify whether the presence of this animal pro-apoptotic Protein modified stress responses and PCD execution, both N. tabacum and A. thaliana plants constitutively expressing flBid have been studied under different stress conditions triggering cell death activation. The results show that the presence of flBid in transgenic plants did not significantly change the responses to abiotic stress (H2O2 or NO) and biotic stress treatments. Moreover, the finding that no Bid active form was present in treated tobacco plants suggests an absence of a proper activation of Bid.
Dai Wu Seol - One of the best experts on this subject based on the ideXlab platform.
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suppression of irf4 by irf1 3 and 7 in noxa expression is a necessary event for ifn γ mediated tumor elimination
Molecular Cancer Research, 2011Co-Authors: Sujan Piya, Ae Ran Moon, Peter I Song, John Hiscott, Dai Wu SeolAbstract:IFN-g plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up- and downregulated Noxa expression, a prodeath BH3 Protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-g is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPSinduced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-g might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-g and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-g alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-g, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity. Mol Cancer Res; � 2011 AACR.
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Suppression of IRF4 by IRF1, 3, and 7 in Noxa Expression Is a Necessary Event for IFN-γ–Mediated Tumor Elimination
Molecular Cancer Research, 2011Co-Authors: Sujan Piya, Ae Ran Moon, Peter I Song, John Hiscott, Dai Wu SeolAbstract:IFN-g plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up- and downregulated Noxa expression, a prodeath BH3 Protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-g is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPSinduced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-g might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-g and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-g alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-g, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity. Mol Cancer Res; � 2011 AACR.
Ingo Ringshausen - One of the best experts on this subject based on the ideXlab platform.
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Recruitment of PKC-Beta to Lipid Rafts Mediates Apoptosis-Resistance in Chronic Lymphocytic Leukemia Expressing Zap-70.
Blood, 2009Co-Authors: Ingo Ringshausen, Michaela Wagner, Gloria Lutzny, Madlene Oelsner, Yvonne Feuerstacke, Thomas Decker, Christian Bogner, Christian Peschel, C Meyer Zum BüschenfeldeAbstract:Abstract 2354 Poster Board II-331 A defect in the programmed cell death, apoptosis, is implemented in the pathogenesis of CLL. About ten years ago, it became evident that patients with CLL can be divided into those with an indolent course of the leukaemia and those which suffer from a more aggressive disease, typically requiring frequent chemotherapy and ultimately develop a chemotherapy-refractory state. The latter group of patients aberrantly express the T-cell associated Protein ZAP-70. The object of this study was to identify the molecular differences underlying the pathogenesis of these two CLL subgroups. To study differences in the apoptotic program we used primary CLL cells derived from untreated ZAP-70 negative and positive patients. Here we show that the expression of ZAP-70 enhances the signals associated with the B-cell receptor (BCR) and recruits Protein kinase C-beta (PKC-beta) into lipid raft domains only in patients with an aggressive variant of the disease. Subsequently, PKC-beta is activated and shuttles from the plasma membrane into the mitochondria. By using co-immunoprecipitation experiments and PKC-beta specific small molecule inhibitors we unravel that the anti-apoptotic Protein Bcl-2 and its antagonistic BH3-Protein Bim are putative substrates for PKC-beta. PKC-beta mediated phosphorylation of Bcl-2 augments its anti-apoptotic function by increasing its ability to sequester more pro-apoptotic Bim. In addition, the phosphorylation of Bim by PKC-beta leads to its proteasomal degradation. Therefore, high levels of phospho-Bcl-2 and low levels of Bim are a hallmark of ZAP-70 positive, aggressive CLL. Importantly, posttranscriptional modifications of Bcl-2 seem to outweigh the absolute expression of Bcl-2 with respect to the suppression of apoptosis. We demonstrate that these cells are strongly protected from chemotherapy-induced cytotoxic stress. Our data indicate that the constitutive activation of PKC-beta is directly involved in the apoptotic defect in ZAP-70 positive CLL. We finally show that targeting PKC-beta is an attractive approach to the treatment of CLL patients. Enzastaurin is a PKC-beta specific inhibitor and currently tested in clinical phase I/II trials for cancer patients. Our data demonstrate that this compound is highly active in CLL cells and augments the cytotoxic effects of standard chemotherapeutic drugs. Our results provide evidence that the constitutive activation of PKC-beta is directly implicated in the pathogenesis of aggressive CLL by altering the function of the apoptosis-regulating Proteins Bcl-2 and Bim. These changes confer cells to a more anti-apoptotic state with aggressiveness of the disease. Targeting PKC-beta with small-molecule inhibitors like Enzastaurin might offer a new therapeutic strategy to control or even cure CLL. Disclosures: No relevant conflicts of interest to declare.
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Recruitment of PKC-betaII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70.
Leukemia, 2009Co-Authors: C Meyer Zum Büschenfelde, Michaela Wagner, Gloria Lutzny, Madlene Oelsner, Yvonne Feuerstacke, Thomas Decker, Christian Bogner, Christian Peschel, Ingo RingshausenAbstract:ZAP-70 is a key signaling molecule in T cells. It couples the antigen-activated T-cell receptor to downstream signaling pathways. Its expression in leukemic B-cells derived from a subgroup of patients with chronic lymphocytic leukemia (CLL) is associated with an aggressive course of the disease. However, its implication for the pathogenesis of aggressive CLL is still unclear. In this study, we show that the expression of ZAP-70 enhances the signals associated with the B-cell receptor, recruiting Protein kinase C-betaII (PKC-betaII) into lipid raft domains. Subsequently, PKC-betaII is activated and shuttles from the plasma membrane to the mitochondria. We unravel that the antiapoptotic Protein Bcl-2 and its antagonistic BH3-Protein Bim(EL) are putative substrates for PKC-betaII. PKC-betaII-mediated phosphorylation of Bcl-2 augments its antiapoptotic function by increasing its ability to sequester more pro-apoptotic Bim(EL.) In addition, the phosphorylation of Bim(EL) by PKC-betaII leads to its proteasomal degradation. These changes confer leukemic cells to a more antiapoptotic state with aggressiveness of the disease. Most importantly, these molecular changes can be therapeutically targeted with the small molecule inhibitor Enzastaurin. We provide evidence that this compound is highly active in leukemic cells and augments the cytotoxic effects of standard chemotherapeutic drugs.
Jin H. Song - One of the best experts on this subject based on the ideXlab platform.
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Abstract LB-487: Pim Protein kinase inhibitors induce the unfolded Protein response and sensitize prostate cancer cells to killing by ABT-737-mediated apoptosis
Molecular and Cellular Biology, 2012Co-Authors: Jin H. Song, Andrew S. KraftAbstract:Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet anticancer efficacy of Pim kinase inhibitors on prostate cancer is unknown. We demonstrate for the first time that a genetically engineered decrease in Pim kinase levels or the addition of Pim kinase small molecule inhibitors (e.g. SMI-4a) to human prostate cancer cells, including LNCaP and PC-3, causes ER stress and activates the unfolded Protein response (UPR) stimulating increases in eIF-2α phosphorylation, ATF-4, CHOP Proteins, and cleavage of XBP-1. Because (1) Bcl-2 family Proteins reside on the ER lumen and play an important role in regulation of XBP-1 splicing, (2) Bcl-2 family members are over expressed in prostate cancer to enhance Pim kinase anti-cancer activity, and (3) Pim kinase inhibitors decrease Mcl-1 and increase Noxa Protein, we treated prostate cancer cell lines with SMI-4a plus the Bcl-2 family antagonist ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′-cap dependent translation and decreasing Protein half life. Additionally, Pim inhibition transcriptionally increased levels of the BH3 Protein Noxa by activating the UPR, lead to eIF2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 Protein activity. Notably, these specific Protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 Protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. We find that the Pim kinase inhibitors and ABT-737 are highly synergistic in killing prostate cancer both in vitro and when used together in a subcutaneous animal model of prostate cancer therapy. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-487. doi:1538-7445.AM2012-LB-487
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Abstract C14: Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737
Cancer Research, 2012Co-Authors: Jin H. Song, Andrew S. KraftAbstract:Abstract Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet Pim kinase inhibitors appear to have only limited effects on prostate cancer cell survival. Since overexpression of Bcl-2 family members are implicated in chemotherapeutic resistance in prostate cancer, we investigated the cooperative effects of Pim kinase inhibition with ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′- cap dependent translation and decreasing Protein half life. Additionally, Pim inhibition transcriptionally increased levels of the BH3 Protein Noxa by activating the unfolded Protein response (UPR), lead to eIF-2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 Protein activity. Notably, these specific Protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 Protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies. Citation Format: Jin H. Song, Andrew S. Kraft. Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C14.
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Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737
Cancer research, 2011Co-Authors: Jin H. Song, Andrew S. KraftAbstract:Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet Pim kinase inhibitors seem to have only limited effects on prostate cancer cell survival. Because overexpression of Bcl-2 family members are implicated in chemotherapeutic resistance in prostate cancer, we investigated the cooperative effects of Pim kinase inhibition with ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′-cap dependent translation and decreasing Protein half life. In addition, Pim inhibition transcriptionally increased levels of the BH3 Protein Noxa by activating the unfolded Protein response (UPR), lead to eIF-2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 Protein activity. Notably, these specific Protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 Protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies. Cancer Res; 72(1); 294–303. ©2011 AACR.