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Overexpression of Par-4 sensitizes TRAIL-induced apoptosis via inactivation of NF-kappaB and Akt signaling pathways in renal cancer cells.

Lee, TJ; Jang, JH; Noh, HJ; Park, EJ; Choi, KS; Kwon, TK
Journal of cellular biochemistry, 109(5):885-895, 2010
Journal Title
Journal of cellular biochemistry
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 TRAIL-resistant 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-kappaB.
MeSH terms
Antigens, CD95/metabolismApoptosis/*drug effectsApoptosis Regulatory Proteins/chemistry/*metabolismCASP8 and FADD-Like Apoptosis Regulating Protein/metabolismCaspase 8/metabolismCell Line, TumorCycloheximide/pharmacologyEnzyme Activation/drug effectsHumansKidney Neoplasms/enzymology/*pathologyLeucine ZippersNF-kappa B/*metabolismPhosphorylation/drug effectsProtein Structure, TertiaryProto-Oncogene Proteins c-akt/*metabolismReceptors, Death Domain/metabolismSequence DeletionSignal Transduction/*drug effectsTNF-Related Apoptosis-Inducing Ligand/*pharmacologyTumor Necrosis Factor-alpha/pharmacologyX-Linked Inhibitor of Apoptosis Protein/metabolism
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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