title: Targeting Bcl-2 stability to sensitize cells harboring oncogenic ras.
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.
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Suthakar
authors.initials: S
authors.lastname: Ganapathy
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.affiliation: Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden.
authors.forename: Junchi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.|The Jiangxi Province Tumor Hospital, Nanchang, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yi
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.|The First Affiliated Hospital of Nanchang University, Nanchang University School of Medicine, Nanchang, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Environmental Medicine, New York University, Tuxedo, NY, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.|Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden.|The First Affiliated Hospital of Nanchang University, Nanchang University School of Medicine, Nanchang, China.
authors.forename: Changyan
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D011905:Genes, ras; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D041701:Swiss 3T3 Cells; D014162:Transfection
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2
keywords: Bcl-2; apoptosis; protein degradation