Abstract 2780: Bortezomib induces autophagy in hepatocellular carcinoma through the inhibition of CIP2A independent of proteasome inhibition.

Abstract

Listen

Translate article

Abstract Previously, we have reported that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates the apoptotic effect of bortezomib in hepatocellular carcinoma (HCC) (Oncogene, 2010). Here, we report the mechanism by which bortezomib induces autophagy in HCC. Our data indicated that bortezomib activated autophagy in a dose- and time- dependent manner in HCC cell lines, including Huh-7, Sk-Hep1, and Hep3B. Bortezomib down-regulated CIP2A, phospho-Akt (P-Akt) and phospho-4EBP1 (P-4EBP1) in a dose- and time- dependent manner in all tested HCC cells. Ectopic expression of CIP2A abolished the effect of bortezomib on autophagy. Cotreatment of bortezomib and calculin A, a PP2A inhibitor, reduced the effect of bortezomib on P-Akt, P-4EBP1, and autophagy. Over-expression of either Akt or 4EBP1 protected cells from bortezomib-induced autophagy. Moreover, we examined the effect of αBtz, a bortezomib derivative that closely resembles bortezomib structurally but with no proteasome activity, in HCC. Interestingly, αBtz demonstrated similar effects to bortezomib on autophagy, CIP2A, P-Akt and P-4EBP1. Furthermore, our in vivo data showed that both bortezomib and αBtz inhibited tumor growth, down-regulated CIP2A, P-Akt and induced autophagy in Huh-7 tumors, suggesting that bortezomib activates autophagy in HCC and this effect is independent to its effect on proteasome. In conclusion, bortezomib induces autophagy in HCC through CIP2A-PP2A-Akt-4EBP1 pathway. Supported by NTUH100P04, NSC99-2314-B-002-017-MY2, NSC100-3112-B-002-013, and NSC100-2325-B-002-036. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2780. doi:1538-7445.AM2012-2780