Overexpression of Par‐4 sensitizes TRAIL‐induced apoptosis via inactivation of NF‐κB and Akt signaling pathways in renal cancer cells

Abstract

The prostate-apoptosis-response-gene-4 (Par-4) is up-regulated in prostate cells undergoing programmed cell death. Furthermore, Par-4 protein has been shown to function as an effector of cell death in response to various apoptotic stimuli that trigger mitochondria and membrane receptor-mediated cell death pathways. In this study, we investigated how Par-4 modulates TRAIL-mediated apoptosis in TRAILresistant Caki cells. Par-4 overexpressing cells were strikingly sensitive to apoptosis induced by TRAIL compared with control cells. Par-4 overexpressing Caki cells treated with TRAIL showed an increased activation of the initiator caspase-8 and the effector caspase-3, together with an enforced cleavage of XIAP and c-FLIP. TRAIL-induced reduction of XIAP and c-FLIP protein levels in Par-4 overexpressing cells was prevented by z-VAD pretreatment. In addition, the surface DR5 protein level was increased in TRAIL-treated Par-4 overexpressing cells. Interestingly, even though a deletion of leucine zipper domain in Par-4 recovered Bcl-2 level to basal level induced by wild type Par-4, it partly decreased sensitivity to TRAIL in Caki cells. In addition, exposure of Caki/Par-4 cells to TRAIL led to reduction of phosphorylated Akt levels, but deletion of leucine zipper domain of Par-4 did not affect these phosphorylated Akt levels. In conclusion, we here provide evidence that ectopic expression of Par-4 sensitizes Caki cells to TRAIL via modulation of multiple targets, including DR5, Bcl-2, Akt, and NF-kB.

The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells

“…Par-4 promotes apoptosis in a variety of cancerous cells, but not in normal mature cells. Par-4 kills human carcinoma cells from the prostate (10, 49), kidney (32, 33), pancreas (3), lung (10), cervix (10), endometrium (48), breast (43), and colon (50). It also has activity against melanoma and leukemia (8, 36, 39, 49).…”

Regulating TRAIL Receptor-Induced Cell Death at the Membrane: A Deadly Discussion

“…Downstream of the DISC, sensitization to TRAIL-induced apoptosis was associated with the deregulation of cell survival proteins including, Bcl-2, Bcl-XL, Mcl-1, HSP27, survivin, IAPs [60, 72-75] or pathways such as AKT and NF-kB [76-79]. …”

Expression and Regulation of Prostate Apoptosis Response-4 (Par-4) in Human Glioma Stem Cells in Drug-Induced Apoptosis

“…Prostrate apoptosis response-4 (Par-4) is a proapoptotic protein and overexpression of Par-4 sensitizes cancer cell lines and tumor cells to cytotoxicity triggered by anticancer drugs [18]. We therefore examined the relationship between the expression of Par-4 and susceptibility to TAM-induced apoptosis.…”

“…Par-4 is downregulated during tumor recurrence in breast cancer and the downregulation is necessary and sufficient to promote recurrence [17]. Endogenous Par-4 is essential for sensitization of cells to diverse apoptotic stimuli, while the expression of Par-4 induced ectopically or triggered by anticancer drugs can selectively cause apoptosis in cancer cells [18]–[20]. In addition to its role as an intracellular proapoptotic protein, other studies have demonstrated that secretory or extracellular Par-4 also induces apoptosis in cancer cells and the mechanism involves binding of Par-4 to GRP78 [21].…”