Abstract
The tumor suppressor protein prostate apoptosis response-4 (PAR-4) is silenced in a subset of human cancers and its down-regulation serves as a mechanism for cancer cell survival following chemotherapy. PAR-4 re-expression selectively causes apoptosis in cancer cells but how its pro-apoptotic functions are controlled and executed precisely is currently unknown. We demonstrate here that UV-induced apoptosis results in a rapid caspase-dependent PAR-4 cleavage at EEPD131G, a sequence that was preferentially recognized by caspase-8. To investigate the effect on cell growth for this cleavage event we established stable cell lines that express wild-type-PAR-4 or the caspase cleavage resistant mutant PAR-4 D131G under the control of a doxycycline-inducible promoter. Induction of the wild-type protein but not the mutant interfered with cell proliferation, predominantly through induction of apoptosis. We further demonstrate that TNFα-induced apoptosis leads to caspase-8-dependent PAR-4-cleavage followed by nuclear accumulation of the C-terminal PAR-4 (132-340) fragment, which then induces apoptosis. Taken together, our results indicate that the mechanism by which PAR-4 orchestrates the apoptotic process requires cleavage by caspase-8.
Highlights
The tumor suppressor protein prostate apoptosis response-4 (PAR-4) was initially discovered as a proapoptotic protein in prostate cancer cells undergoing apoptosis [1]
In summary we have demonstrated that PAR-4 is a novel caspase-8 substrate and provide evidence that PAR-4 cleavage downstream of caspase-8 is required for TNFα induced apoptosis
Previous findings indicated that PAR-4 selectively induces apoptosis in cancer cell lines including HeLa cells [11]
Summary
The tumor suppressor protein prostate apoptosis response-4 (PAR-4) was initially discovered as a proapoptotic protein in prostate cancer cells undergoing apoptosis [1]. Consistent with its role as a tumor suppressor PAR-4 expression is silenced in a well-defined subset of cancers including renal cancers, neuroblastomas, endometrial carcinomas, lung adenocarcinomas, and prostate carcinomas [3,4,5,6,7]. Recent findings by Alvarez and coworkers document that down-regulation of PAR-4 is necessary for tumor cell survival and recurrence of breast cancer following targeted therapy in mouse models and in patients [8]. Ras expression has been shown to require the MEK/ ERK MAPK pathway [9] and consistent with this Par-4 knockout mice cooperate with oncogenic Kras to induce lung adenocarcinomas [6]. Par-4 was found to be an essential regulator of HrasG12V-dependent oncogenic growth in a genome-wide RNAi screen [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
