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.
Highlights
IntroductionBcl-2 family consists of members that are able either to promote cell survival (such as Bcl-2 and Bcl-XL) or apoptosis (for example, Bax or Bak) [1, 2]
Bcl-2 family consists of members that are able either to promote cell survival or apoptosis [1, 2]
We demonstrated that Bcl-2 degradation appeared to be involved in apoptosis triggered by GO6976 or shRNA-protein kinase C (PKC) α plus β in Swiss3T3 cells transformed by v-K-ras or murine lung cancer LKR cells harboring oncogenic K-ras
Summary
Bcl-2 family consists of members that are able either to promote cell survival (such as Bcl-2 and Bcl-XL) or apoptosis (for example, Bax or Bak) [1, 2]. Levels or balances between the pro-and anti-apoptotic factors determine thresholds of cells for the induction of apoptosis. Bcl-2 resides in the endoplasmic reticulum and mitochondria [3, 4]. Through binding to Bax or regulating the membrane permeability of the mitochondria, Bcl-2 was shown to interfere with releasing of the mitochondrial apoptotic factors (for example, Bax or cytochrome c) to the cytosol, and thereby suppressed cell death process [3, 5, 6]. The mechanisms by which Bcl-2 is being regulated and further affects the susceptibility of cells to apoptosis are not fully understood yet
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