Research Papers:
Targeting Bcl-2 stability to sensitize cells harboring oncogenic ras
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Abstract
Bo Peng1,*, Suthakar Ganapathy1,*, Ling Shen1, Junchi Huang2, Bo Yi1,3, Xiaodong Zhou1,4, Wei Dai5, Changyan Chen1,2,4
1Center for Drug Discovery, Northeastern University, Boston, MA, USA
2Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden
3The Jiangxi Province Tumor Hospital, Nanchang, China
4The First Affiliated Hospital of Nanchang University, Nanchang University School of Medicine, Nanchang, China
5Department of Environmental Medicine, New York University, Tuxedo, NY, USA
*These authors have contributed equally to this work
Correspondence to:
Changyan Chen, e-mail: [email protected]
Keywords: apoptosis, Bcl-2, protein degradation
Received: March 11, 2015 Accepted: May 13, 2015 Published: May 25, 2015
ABSTRACT
The pro-survival factor Bcl-2 and its family members are critical determinants of the threshold of the susceptibility of cells to apoptosis. Studies are shown that cells harboring an oncogenic ras were extremely sensitive to the inhibition of protein kinase C (PKC) and Bcl-2 could antagonize this apoptotic process. However, it remains unrevealed how Bcl-2 is being regulated in this apoptotic process. In this study, we investigate the role of Bcl-2 stability in sensitizing the cells harboring oncogenic K-ras to apoptosis triggered by PKC inhibitor GO6976. We demonstrated that Bcl-2 in Swiss3T3 cells ectopically expressing or murine lung cancer LKR cells harboring K-ras rapidly underwent ubiquitin-dependent proteasome pathway after the treatment of GO6976, accompanied with induction of apoptosis. In this process, Bcl-2 formed the complex with Keap-1 and Cul3. The mutation of serine-17 and deletion of BH-2 or 4 was required for Bcl-2 ubiquitination and degradation, which elevate the signal threshold for the induction of apoptosis in the cells following PKC inhibition. Thus, Bcl-2 appears an attractive target for the induction of apoptosis by PKC inhibition in cancer cells expressing oncogenic K-ras.
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PII: 4084