Oncotarget

Research Papers:

Targeting Bcl-2 stability to sensitize cells harboring oncogenic ras

Bo Peng _, Suthakar Ganapathy, Ling Shen, Junchi Huang, Bo Yi, Xiaodong Zhou, Wei Dai and Changyan Chen

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Oncotarget. 2015; 6:22328-22337. https://doi.org/10.18632/oncotarget.4084

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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: c.changyan@neu.edu

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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