?B-crystallin promotes oncogenic transformation and inhibits caspase activation in cells primed for apoptosis by Rb inactivation.

ABSTRACT: The retinoblastoma (Rb) tumor suppressor gene is frequently inactivated in cancer, resulting in deregulated activation of E2F transcription factors, which promote S-phase entry, p53-dependent and p53-independent apoptosis. Transformed cells evade p53-dependent apoptosis initiated by Rb inactivation by TP53 mutation. However, the mechanisms by which cancer cells circumvent p53-independent apoptosis in this context are poorly understood. Because Rb inactivation primes cells for apoptosis by p53-independent induction of procaspases, we postulated that ?B-crystallin, an inhibitor of procaspase-3 activation, would suppress caspase activation in cells with combined Rb and p53 inactivation. Notably, ?B-crystallin is commonly expressed in ER/PR/HER2 "triple-negative" breast carcinomas characterized by frequent Rb loss and TP53 mutation. We report that ?B-crystallin (-/-) knock out (KO) MEFs immortalized by dominant negative (DN) p53 are resistant to transformation by the adenovirus E1A oncoprotein, which inactivates Rb, while wild-type (WT) MEFs are readily transformed by DN p53 and E1A. ?B-crystallin (-/-) KO MEFs stably expressing DN p53 and E1A were more sensitive to chemotherapy-induced caspase-3 activation and apoptosis than the corresponding WT MEFs, despite comparable induction of procaspases by E1A. Similarly, silencing Rb in WT and ?B-crystallin (-/-) KO MEFs immortalized by DN p53 increased procaspase levels and sensitized ?B-crystallin (-/-) KO MEFs to chemotherapy. Furthermore, silencing ?B-crystallin in triple-negative breast cancer cells, which lack Rb and express mutant p53, enhanced chemotherapy sensitivity compared to non-silencing controls. Our results indicate that ?B-crystallin inhibits caspase activation in cells primed for apoptosis by Rb inactivation and plays a novel oncogenic role in the context of combined Rb and p53 inactivation.

SUBMITTER: Petrovic V 

PROVIDER: S-EPMC4106679 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature