Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA.
Int J Oncol. 2010 Apr;36(4):883-8. doi: 10.3892/ijo_00000566.
Protein kinase C epsilon (PKCepsilon) is a transforming oncogene and an important anti-apoptotic protein. We previously demonstrated that overexpression of PKCepsilon in MCF-7 breast cancer cells caused an increase in anti-apoptotic Bcl-2 and a decrease in pro-apoptotic Bid, attenuating tumor necrosis factor-alpha (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The objective of our present study was to determine the mode of induction of Bcl-2 by PKCepsilon in breast cancer cells. siRNA silencing of either PKCepsilon or Akt in MCF-7 cells, which overexpress Akt, decreased Bcl-2 protein and mRNA levels. However, knockdown of PKCepsilon, but not Akt, led to the decrease in Bcl-2 at both protein and mRNA levels in MDA-MB-231 breast cancer cells, which overexpress PKCepsilon but contain little constitutively-active Akt. Knockdown of PKCepsilon decreased phosphorylation of cAMP response element-binding protein (CREB) at Ser133 in MDA-MB-231 cells, and depletion of CREB by siRNA decreased Bcl-2 at both the protein and mRNA levels. In addition, knockdown of CREB sensitized MDA-MB-231 cells to TRAIL-mediated cell death. These results suggest that PKCepsilon regulates Bcl-2 induction through activation of the transcription factor CREB.
蛋白激酶 C ɛ (PKCɛ) 是一种转化癌基因和重要的抗凋亡蛋白。我们之前的研究表明，PKCɛ 在 MCF-7 乳腺癌细胞中的过表达导致抗凋亡 Bcl-2 的增加和促凋亡 Bid 的减少，从而减弱肿瘤坏死因子-α (TNF)-相关凋亡诱导配体 (TRAIL) 介导的细胞凋亡。本研究的目的是确定 PKCɛ 在乳腺癌细胞中诱导 Bcl-2 的方式。在高表达 Akt 的 MCF-7 细胞中，用 siRNA 沉默 PKCɛ 或 Akt，均可降低 Bcl-2 蛋白和 mRNA 水平。然而，在高表达 PKCɛ 但含有少量组成性激活 Akt 的 MDA-MB-231 乳腺癌细胞中，PKCɛ 的敲低导致 Bcl-2 的蛋白和 mRNA 水平降低。PKCɛ 的敲低降低了 MDA-MB-231 细胞中 cAMP 反应元件结合蛋白 (CREB) Ser133 的磷酸化，siRNA 耗尽 CREB 降低了 Bcl-2 的蛋白和 mRNA 水平。此外，CREB 的敲低使 MDA-MB-231 细胞对 TRAIL 介导的细胞死亡敏感。这些结果表明，PKCɛ 通过激活转录因子 CREB 来调节 Bcl-2 的诱导。
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