Abstract 1022: PI3-kinase inhibition enhances ABT-737-induced apoptosis in colorectal cancer cell lines

Abstract

Abstract The PI3-kinase signalling pathway is widely reported to promote survival, proliferation and migration. This pathway is up-regulated in several solid tumours by a host of different mechanisms, including PTEN deletion, RAS or PIK3CA mutation and aberrant activation of receptor tyrosine kinases. As such, inhibitors of PI3-kinase and its down-stream effectors are of great interest as tractable anti-cancer agents. The effect of PI3-kinase inhibition was investigated in colorectal cancer cell lines and demonstrated that, while PI3-kinase inhibition by itself did not cause cell death, it enhanced apoptosis induced by the BH3 mimetic ABT-737 (assessed by nuclear fragmentation, caspase 3 cleavage and phosphatidylserine exposure). Furthermore, ABT-737 and PI3-kinase inhibition caused increased level of Bak activating conformational change compared to ABT-737 alone, suggesting that the effect of PI3-kinase inhibition is up-stream of cytochrome C release. PI3-kinase inhibition did not alter the expression level of Bcl-2 family members, but co-immunoprecipitation revealed that it increased the amount of Bim bound to Bcl-xL. No change was seen in the binding of other BH3 only proteins or of Bax or Bak to ABT-737 targets Bcl-2 or Bcl-xL. ABT-737-induced apoptosis was independent of AKT and mTOR signalling as it was unaffected by the inhibitors AKTi1/2 and rapamycin respectively. A model is proposed whereby ABT-737 interrupts PI-3K inhibition-induced Bim/Bcl-xL complexes to promote apoptosis via Bax/Bak activation. Function testing experiments are underway to interrogate this model. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1022.