Targeting Bcl-2 stability to sensitize cells harboring oncogenic ras.
Targeting Bcl-2 stability to sensitize cells harboring oncogenic ras.
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DOI：
10.18632/oncotarget.4084
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发表时间：
2015-09-08
期刊：
影响因子：
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通讯作者：
Chen C
中科院分区：
文献类型：
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作者：
Peng B;Ganapathy S;Shen L;Huang J;Yi B;Zhou X;Dai W;Chen C
促生存因子Bcl-2及其家族成员是细胞凋亡敏感性阈值的关键决定因素。研究表明，具有致癌基因ras的细胞对蛋白激酶C（PKC）的抑制非常敏感，Bcl-2可以拮抗这种凋亡过程。然而，Bcl-2在凋亡过程中是如何被调节的，这一点还没有被揭示。在这项研究中，我们研究Bcl-2的稳定性在敏感性的细胞窝藏致癌K-ras蛋白激酶C抑制剂GO 6976引发的凋亡的作用。我们证明，Bcl-2在Swiss 3 T3细胞异位表达或小鼠肺癌LKR细胞窝藏K-ras迅速进行泛素依赖的蛋白酶体途径后，GO 6976处理，伴随着诱导凋亡。在此过程中，Bcl-2与Keap-1和Cul 3形成复合物。Bcl-2的泛素化和降解需要丝氨酸17的突变和BH-2或4的缺失，这提高了PKC抑制后诱导细胞凋亡的信号阈值。因此，Bcl-2似乎是一个有吸引力的目标，诱导细胞凋亡的PKC抑制癌细胞表达致癌K-ras。
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.