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C-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer cells.

ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resistant tumors are essential for effective cancer therapies. Here, we show that c-Fos functions as a proapoptotic agent by repressing the antiapoptotic molecule c-FLIP(L). c-Fos binds the c-FLIP(L) promoter, represses its transcriptional activity, and reduces c-FLIP(L) mRNA and protein levels. Therefore, c-Fos is a key regulator of c-FLIP(L), and activation of c-Fos determines whether a cancer cell will undergo cell death after TRAIL treatment. Strategies to activate c-Fos or inhibit c-FLIP(L) may potentiate TRAIL-based proapoptotic therapies.

SUBMITTER: Zhang X

PROVIDER: S-EPMC2941899 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer cells.

Zhang Xiaoping X Zhang Liang L Yang Hongmei H Huang Xu X Otu Hasan H Libermann Towia A TA DeWolf William C WC Khosravi-Far Roya R Olumi Aria F AF

Cancer research 20071001 19

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resistant tumors are essential for effective cancer therapies. Here, we show that c-Fos functions as a proapoptotic agent by repressing the antiapoptotic mol ...[more]

PMID: 17909052

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Glucosamine Enhances TRAIL-Induced Apoptosis in the Prostate Cancer Cell Line DU145.

Project description:Background: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells in cancer patients. However, patients often develop TRAIL resistance; thus, agents that can sensitize cells to TRAIL therapy would be beneficial clinically. Methods: Immunoblotting, flow cytometry, confocal microscopy, qPCR and caspase 8 activity assays were used to investigate whether glucosamine (GlcN) can sensitize cancer cells to TRAIL thereby enhancing apoptosis and potentially improving clinical response. Results: GlcN sensitized DU145 cells to TRAIL-induced apoptosis but did not increase death receptor 5 (DR5) cell surface expression. Once treated, these cells responded to TRAIL-induced apoptosis through both extrinsic and intrinsic apoptotic pathways as evidenced by the cleavage of both caspases 8 and 9. The combination of GlcN and TRAIL suppressed the expression of key anti-apoptotic factors cFLIP, BCL-XL, MCL-1 and XIAP and translocated BAK to the mitochondrial outer membrane thereby facilitating cytochrome C and SMAC release. In addition to the activation of apoptotic pathways, TRAIL-mediated inflammatory responses were attenuated by GlcN pretreatment reducing nuclear NF-kB levels and the expression of downstream target genes IL-6 and IL-8. Conclusions: GlcN/TRAIL combination could be a promising strategy for treating cancers by overcoming TRAIL resistance and abrogating TRAIL-induced inflammation.

| S-EPMC6963486 | biostudies-literature

Retinoic acid enhances TRAIL-induced apoptosis in cancer cells by upregulating TRAIL receptor 1 expression.

Project description:Many human cancer cells are sensitive to killing by the proapoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL), which is under study for cancer treatment in clinical trials. The TRAIL receptor (TRAIL-R1; also known as death receptor 4) is a transmembrane receptor that mediates TRAIL-induced apoptosis in cancer cells. In this study, we show that retinoids sensitize cancer cells to TRAIL-induced apoptosis by upregulating expression of TRAIL-R1. All-trans retinoic acid (ATRA) upregulated TRAIL-R1 expression in human cancer cells at the transcriptional level. The ability of ATRA to activate TRAIL-R1 expression was inhibited by retinoic acid receptor (RAR) antagonists or siRNAs, but augmented by several RAR agonists. In analyzing how ATRA induces RAR-dependent transcriptional upregulation of TRAIL-R1, we identified 2 putative retinoic acid response elements termed Pal-17 (a palindrome separated by 17 bases) and DR-11 (a direct repeat separated by 11 bases) in the 5'-flanking region of TRAIL-R1 gene. Deletion of DR-11, but not Pal-17, abrogated the ability of ATRA to stimulate TRAIL-R1 promoter activity. Consistent with this observation, RAR binding to DR-11, but not to Pal-17, was detected by chromatin immunoprecipitation assay in ATRA-treated cells, arguing that DR-11 was responsible for ATRA-mediated activation of the TRAIL-R1 gene. ATRA augmented TRAIL-induced apoptosis of cancer cells, and this activity was attenuated by a blockade to upregulation of TRAIL-R1 expression. Taken together, our findings establish that ATRA accentuates TRAIL-induced apoptosis, reveal a novel mechanism by which retinoids modulate apoptosis, and suggest a novel strategy to augment the anti-cancer activity of TRAIL.

| S-EPMC3151668 | biostudies-literature

Histone Deacetylase Inhibitors Sensitize TRAIL-Induced Apoptosis in Colon Cancer Cells.

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a promising anti-cancer therapeutic. However, many cancers have been found to be or to become inherently resistant to TRAIL. A combination of epigenetic modifiers, such as histone deacetylase inhibitors (HDACi's), with TRAIL was effective to overcome TRAIL resistance in some cancers. Broad spectrum HDACi's, however, show considerable toxicity constraining clinical use. Since overexpression of class I histone deacetylase (HDAC) has been found in colon tumors relative to normal mucosa, we have focused on small spectrum HDACi's. We have now tested agonistic receptor-specific TRAIL variants rhTRAIL 4C7 and DHER in combination with several class I specific HDACi's on TRAIL-resistant colon cancer cells DLD-1 and WiDr. Our data show that TRAIL-mediated apoptosis is largely improved in WiDr cells by pre-incubation with Entinostat-a HDAC1, 2, and 3 inhibitor- and in DLD-1 cells by RGFP966-a HDAC3-specific inhibitor- or PCI34051-a HDAC8-specific inhibitor. We are the first to report that using RGFP966 or PCI34051 in combination with rhTRAIL 4C7 or DHER represents an effective cancer therapy. The intricate relation of HDACs and TRAIL-induced apoptosis was confirmed in cells by knockdown of HDAC1, 2, or 3 gene expression, which showed more early apoptotic cells upon adding rhTRAIL 4C7 or DHER. We observed that RGFP966 and PCI34051 increased DR4 expression after incubation on DLD-1 cells, while RGFP966 induced more DR5 expression on WiDr cells, indicating a different role for DR4 or DR5 in these combinations. At last, we show that combined treatment of RGFP966 with TRAIL variants (rhTRAIL 4C7/DHER) increases apoptosis on 3D tumor spheroid models.

| S-EPMC6562715 | biostudies-literature

Osteoprotegerin (OPG) protects ovarian cancer cells from TRAIL-induced apoptosis but does not contribute to malignant ascites-mediated attenuation of TRAIL-induced apoptosis.

Project description:UnlabelledBackgroundResistance to apoptosis is a major problem in ovarian cancer and correlates with poor prognosis. Osteoprotegerin (OPG) is a secreted factor in malignant ascites and acts as a decoy receptor for receptor activator of NF-?B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL promotes apoptosis in ovarian cancer cells. Ovarian cancer ascites attenuate TRAIL-induced apoptosis raising the possibility that OPG contained in ascites may abrogate the anti-tumor activity of TRAIL.MethodsDetermination of OPG levels in ascites was measured by ELISA. Effect of OPG on TRAIL-induced cell death was determined by XTT and colony forming assays in ovarian cancer cell lines and primary tumor cells. Apoptosis was assessed by ELISA.ResultsWe found that recombinant OPG and malignant ascites attenuates TRAIL-induced cell death and apoptosis in a dose-dependent manner in ovarian cancer cell lines and primary ovarian tumor cells. OPG is present at high levels in the ascites of patients with ovarian cancer. We found a positive correlation between the levels of OPG in ascites and the ability of the ascites to attenuate TRAIL-induced cell death. The anti-apoptotic effect of ascites was not reversed by co-incubation with an OPG blocking antibody.ConclusionsOPG and malignant ascites protect ovarian cancer cells from TRAIL-induced apoptosis. Although malignant ascites contain high levels of OPG, OPG is not a critical component that contributes to ascites-mediated attenuation of TRAIL-induced apoptosis.

| S-EPMC3507713 | biostudies-literature

Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells.

Project description:The proapoptotic protein, prostate apoptosis response-4 (Par-4), acts as a tumor suppressor in prostate cancer cells. The serine/threonine kinase casein kinase 2 (CK2) has a well-reported role in prostate cancer resistance to apoptotic agents or anticancer drugs. However, the mechanistic understanding on how CK2 supports survival is far from complete. In this work, we demonstrate both in rat and humans that (i) Par-4 is a new substrate of the survival kinase CK2 and (ii) phosphorylation by CK2 impairs Par-4 proapoptotic functions. We also unravel different levels of CK2-dependent regulation of Par-4 between species. In rats, the phosphorylation by CK2 at the major site, S124, prevents caspase-mediated Par-4 cleavage (D123) and consequently impairs the proapoptotic function of Par-4. In humans, CK2 strongly impairs the apoptotic properties of Par-4, independently of the caspase-mediated cleavage of Par-4 (D131), by triggering the phosphorylation at residue S231. Furthermore, we show that human Par-4 residue S231 is highly phosphorylated in prostate cancer cells as compared with their normal counterparts. Finally, the sensitivity of prostate cancer cells to apoptosis by CK2 knockdown is significantly reversed by parallel knockdown of Par-4. Thus, Par-4 seems a critical target of CK2 that could be exploited for the development of new anticancer drugs.

| S-EPMC4040712 | biostudies-literature

Glycogen synthase kinase-3 inhibition sensitizes pancreatic cancer cells to TRAIL-induced apoptosis.

Project description:Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induces apoptosis in a variety of cancer cell lines with little or no effect on normal cells. However, its effect is limited as some cancers including pancreatic cancer show de novo resistance to TRAIL induced apoptosis. In this study we report that GSK-3 inhibition using the pharmacologic agent AR-18, enhanced TRAIL sensitivity in a range of pancreatic and prostate cancer cell lines. This sensitization was found to be caspase-dependent, and both pharmacological and genetic knock-down of GSK-3 isoforms resulted in apoptotic features as shown by cleavage of PARP and caspase-3. Elevated levels of reactive oxygen intermediates and disturbance of mitochondrial membrane potential point to a mitochondrial amplification loop for TRAIL-induced apoptosis after GSK-3 inhibition. Consistent with this, overexpression of anti-apoptotic mitochondrial targets such as Bcl-XL, Mcl-1, and Bcl-2 rescued PANC-1 and PPC-1 cells from TRAIL sensitization. However, overexpression of the caspase-8 inhibitor CrmA also inhibited the sensitizing effects of GSK-3 inhibitor, suggesting an additional role for GSK-3 that inhibits death receptor signaling. Acute treatment of mice bearing PANC-1 xenografts with a combination of AR-18 and TRAIL also resulted in a significant increase in apoptosis, as measured by caspase-3 cleavage. Sensitization to TRAIL occurred despite an increase in ?-catenin due to GSK-3 inhibition, suggesting that the approach might be effective even in cancers with dysregulated ?-catenin. These results suggest that GSK-3 inhibitors might be effectively combined with TRAIL for the treatment of pancreatic cancer.

| S-EPMC3400624 | biostudies-literature

MADD knock-down enhances doxorubicin and TRAIL induced apoptosis in breast cancer cells.

Project description:The Map kinase Activating Death Domain containing protein (MADD) isoform of the IG20 gene is over-expressed in different types of cancer tissues and cell lines and it functions as a negative regulator of apoptosis. Therefore, we speculated that MADD might be over-expressed in human breast cancer tissues and that MADD knock-down might synergize with chemotherapeutic or TRAIL-induced apoptosis of breast cancer cells. Analyses of breast tissue microarrays revealed over-expression of MADD in ductal and invasive carcinomas relative to benign tissues. MADD knockdown resulted in enhanced spontaneous apoptosis in human breast cancer cell lines. Moreover, MADD knockdown followed by treatment with TRAIL or doxorubicin resulted in increased cell death compared to either treatment alone. Enhanced cell death was found to be secondary to increased caspase-8 activation. These data indicate that strategies to decrease MADD expression or function in breast cancer may be utilized to increase tumor cell sensitivity to TRAIL and doxorubicin induced apoptosis.

| S-EPMC3574069 | biostudies-literature

Androgens regulate TRAIL-induced cell death in prostate cancer cells via multiple mechanisms.

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising therapeutic agent for prostate cancer because it selectively induces apoptosis in cancer cells but not in normal cells. Previous reports have suggested that androgens regulate TRAIL-induced apoptosis in prostate cancer cells. However, there are discrepancies between these reports of how androgens affect TRAIL-induced cell death. To clarify the role of androgens on TRAIL-induced apoptosis in prostate cancer cells, we investigated the effects of androgen on TRAIL-induced cell death in a dose-response manner. Our results showed that although androgens sensitize LNCaP cells to TRAIL-induced apoptosis, this effect is dose-dependent and biphasic. We found that low levels of androgen are superior to high levels of androgen in term of sensitizing LNCaP cells to TRAIL. We also found that upregulation of DR5 (TRAIL-R2) expression by androgens is critical for sensitizing LNCaP cells to TRAIL. However, low levels of androgen are sufficient to induce DR5 expression and sensitize LNCaP cells to TRAIL-induced cell death. High levels of androgen alter the TRADD/RIP1 ratio, which may contribute to NF-?B activation and sequentially inhibit TRAIL-induced apoptosis.

| S-EPMC3676898 | biostudies-literature

Alternol Sensitizes Renal Carcinoma Cells to TRAIL-Induced Apoptosis.

Project description:Purpose: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, can selectively induce cancer cell death while sparing normal cells. However, the application of TRAIL-based antitumor therapies has been hindered due to drug resistance. Alternol is a new compound isolated from microbial fermentation that possesses antitumor activity in different tumors. In our research, we discovered that alternol can sensitize TRAIL-induced apoptosis in renal carcinoma cells (RCCs). Materials and Methods: Cytotoxic activity was measured by MTT assay. Apoptosis was probed using the PI/annexin V method. Real-time PCR and western blot were used to test the levels of mRNA and protein, respectively. Luciferase assay was used to investigate whether CHOP regulated the expression of death receptor (DR) 5 through transcription. A xenogeneic tumor transplantation model was used to evaluate the anticancer effects of alternol/TRAIL in vivo. Results: When the mechanisms were investigated, we discovered that alternol increased DR5 expression. DR5 knockdown by siRNA eliminated the enhanced effect of alternol on TRAIL-mediated apoptosis. Alternol reduced the expression of antiapoptotic proteins and increased the levels of proapoptotic proteins. Moreover, alternol increased the level of CHOP, which is necessary for the enhancing effect of alternol on TRAIL-induced apoptosis, given that downregulation of CHOP abrogated the synergistic effect. DR5 upregulation induced by alternol required the production of reactive oxygen species (ROS). Removing ROS inhibited the induction of DR5 and blocked the antiapoptotic proteins induced by alternol. Conclusion: Taken together, our research suggested that alternol increased TRAIL-mediated apoptosis via inhibiting antiapoptotic proteins and upregulating DR5 levels via ROS generation and the CHOP pathway.

| S-EPMC8026879 | biostudies-literature

Proapoptotic protein Smac mediates apoptosis in cisplatin-resistant ovarian cancer cells when treated with the anti-tumor agent AT101.

Project description:Chemoresistance of ovarian cancer has been previously attributed to the expression and activation of Bcl-2 family proteins. BH3-mimetic molecules possessing potential anticancer activity are able to inhibit antiapoptotic Bcl-2 family proteins. AT101 (R-(-)-gossypol), a natural BH3-mimetic molecule, has shown anti-tumor activity as a single agent and in combination with standard anticancer therapies in a variety of tumor models. Here, we report the effect of AT101 on apoptosis in cisplatin-resistant ovarian cancer cells and identify the major molecular events that determine sensitivity. AT101 induced cell apoptosis by activating Bax through a conformational change, translocation, and oligomerization. The inhibition of Bax expression only partially prevented caspase-3 cleavage. However, the gene silencing of Bax had no effect on mitochondrial Smac release. Further experiments demonstrated that Smac reduction inhibited caspase-3 activation and attenuated cell apoptosis. More importantly, the inhibition of Smac or overexpression of XIAP attenuated Bax activation in ovarian cells. Furthermore, our data indicate that the Akt-p53 pathway is involved in the regulation of Smac release. Taken together, our data demonstrate the role of Smac and the molecular mechanisms of AT101-induced apoptosis of chemoresistant ovarian cancer cells. Our findings suggest that AT101 not only triggers Bax activation but also induces mitochondrial Smac release. Activated Smac can enhance Bax-mediated cellular apoptosis. Therefore, Smac mediates Bax activation to determine the threshold for overcoming cisplatin resistance in ovarian cancer cells.

| S-EPMC3249122 | biostudies-other

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