alpha B-Crystallin promotes oncogenic transformation and inhibits caspase activation in cells primed for apoptosis by Rb inactivation

作者：Petrovic Vladimir; Malin Dmitry; Cryns Vincent L^*

来源：Breast Cancer Research and Treatment, 2013, 138(2): 415-425.

DOI：10.1007/s10549-013-2465-6

• alpha B-Crystallin
• Apoptosis
• Oncogenic transformation
• Caspases
• Rb

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 alpha B-crystallin, an inhibitor of procaspase-3 activation, would suppress caspase activation in cells with combined Rb and p53 inactivation. Notably, alpha B-crystallin is commonly expressed in ER/PR/HER2 "triple-negative" breast carcinomas characterized by frequent Rb loss and TP53 mutation. We report that alpha 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. alpha 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 alpha B-crystallin (-/-) KO MEFs immortalized by DN p53 increased procaspase levels and sensitized alpha B-crystallin (-/-) KO MEFs to chemotherapy. Furthermore, silencing alpha 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 alpha 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.

• 出版日期2013-4