Abstract
BackgroundProstate apoptosis response-4 (Par-4) is a tumor-suppressor protein that selectively activates and induces apoptosis in cancer cells, but not in normal cells. The cancer specific pro-apoptotic function of Par-4 is encoded in its centrally located SAC (Selective for Apoptosis induction in Cancer cells) domain (amino acids 137–195). The SAC domain itself is capable of nuclear entry, caspase activation, inhibition of NF-κB activity, and induction of apoptosis in cancer cells. However, the precise mechanism(s) of how the SAC domain is released from Par-4, in response to apoptotic stimulation, is not well explored.ResultsIn this study, we demonstrate for the first time that sphingosine (SPH), a member of the sphingolipid family, induces caspase-dependant cleavage of Par-4, leading to the release of SAC domain containing fragment from it. Par-4 is cleaved at the EEPD131G site on incubation with caspase-3 in vitro, and by treating cells with several anti-cancer agents. The caspase-3 mediated cleavage of Par-4 is blocked by addition of the pan-caspase inhibitor z-VAD-fmk, caspase-3 specific inhibitor Ac-DEVD-CHO, and by introduction of alanine substitution for D131 residue. Moreover, suppression of SPH-induced Akt dephosphorylation also abrogated the caspase dependant cleavage of Par-4.ConclusionEvidence provided here shows that Par-4 is cleaved by caspase-3 during SPH-induced apoptosis. Cleavage of Par-4 leads to the generation of SAC domain containing fragment which may possibly be essential and sufficient to induce or augment apoptosis in cancer cells.
Highlights
Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that selectively activates and induces apoptosis in cancer cells, but not in normal cells
Par-4 is cleaved during SPH-induced apoptosis in Jurkat cells Recently, Chaudhry and colleagues demonstrated that Par-4 is a novel substrate for caspase-3 during cisplatininduced apoptosis in ovarian cancer cells [30]
We sought to extend this observation and to determine whether activation of the caspase cascade induced by SPH, plays a role in the cleavage of Par-4 protein in Jurkat cells
Summary
Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that selectively activates and induces apoptosis in cancer cells, but not in normal cells. Programmed cell death or apoptosis, plays an important role in biology; such as differentiation, control of cell number, and removal of damaged cells It is implicated in cancer, autoimmune and neurodegenerative diseases [1,2]. Apoptosis is characterized by the activation of multifunctional, highly regulated family of cysteinedependent aspartate-directed protease enzymes called caspases These enzymes catalyze biologically diverse set of reactions and play a critical role in the initiation and execution of apoptosis. A large number of substrates for caspases have already been identified These include structural proteins such as nuclear lamins, proteins involved in the DNA repair mechanism such as poly (ADP-ribose) polymerase (PARP), and tumor suppressor protein such as p53 [4,5]
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