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

• Authors: Vladimir Petrovic, Dmitry Malin, Vincent L Cryns
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 138 Issue 2 Pg. 415-25 (Apr 2013) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 23471649 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenovirus E1A Proteins
• Antineoplastic Agents
• RNA, Small Interfering
• Retinoblastoma Protein
• Tumor Suppressor Protein p53
• alpha-Crystallin B Chain
• Doxorubicin
• Casp3 protein, mouse
• Caspase 3
• Paclitaxel

Topics

• Adenovirus E1A Proteins (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Caspase 3 (metabolism)
• Cell Proliferation
• Cell Transformation, Neoplastic (metabolism)
• Cells, Cultured
• Doxorubicin (pharmacology)
• Enzyme Activation
• Epithelial Cells (metabolism)
• Female
• Gene Knockdown Techniques
• Humans
• Mammary Glands, Human (pathology)
• Mice
• Mice, Knockout
• Paclitaxel (pharmacology)
• RNA, Small Interfering (genetics)
• Retinoblastoma Protein (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics)
• alpha-Crystallin B Chain (genetics, metabolism)