PI3K inhibition potentiates Bcl-2-dependent apoptosis in renal carcinoma cells
Article first published online: 7 FEB 2013
© 2013 The Authors Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Journal of Cellular and Molecular Medicine
Volume 17, Issue 3, pages 377–385, March 2013
How to Cite
Zhu, S., Cohen, M. B., Bjorge, J. D., Mier, J. W. and Cho, D. C. (2013), PI3K inhibition potentiates Bcl-2-dependent apoptosis in renal carcinoma cells. Journal of Cellular and Molecular Medicine, 17: 377–385. doi: 10.1111/jcmm.12019
- Issue published online: 28 MAR 2013
- Article first published online: 7 FEB 2013
- Manuscript Accepted: 28 DEC 2012
- Manuscript Received: 17 JUL 2012
- NIH. Grant Numbers: 2P50CA101942, 1K08CA142890
Vol. 18, Issue 7, 1490, Article first published online: 30 JUL 2014
- renal carcinoma cell;
Inhibitors of PI3-K/Akt are currently being assessed clinically in patients with advanced RCC. Identification of therapeutic strategies that might enhance the efficacy of PI3-K/Akt inhibitors is therefore of great interest. As PI3-K inhibition would be expected to have many pro-apoptotic effects, we hypothesized that there may be unique synergy between PI3-K inhibitors and BH3-mimetics. Towards this end, we assessed the combination of the PI3K inhibitor LY 294002 and the Bcl-2 family inhibitor ABT-737 in RCC cell lines. We found that the combinatorial treatment with these agents led to a significant increase in PARP cleavage and cell death in all RCC cell lines. The synergized cell death was correlated with decreased levels of Mcl-1 and XIAP, and increased levels in Bim, and appears critically dependent upon the activation of caspase 3 and 8. The enhanced lethality observed with the combination also appears dependent upon the regulation of XIAP, Mcl-1 and Bim levels. Our results suggest that the combination of PI3-K inhibitors with BH3-mimetics may be a viable therapeutic strategy in RCC.