Simultaneous knock-down of Bcl-xL and Mcl-1 induces apoptosis through Bax activation in pancreatic cancer cells.
Simultaneous knock-down of Bcl-xL and Mcl-1 induces apoptosis through Bax activation in pancreatic cancer cells.
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DOI：
10.1016/j.bbamcr.2013.08.006
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发表时间：
2013-12
影响因子：
5.1
通讯作者：
Eibl, Guido
中科院分区：
文献类型：
--
作者：
Takahashi, Hiroki;Chen, Monica C.;Hung Pham;Matsuo, Yoichi;Ishiguro, Hideyuki;Reber, Howard A.;Takeyama, Hiromitsu;Hines, Oscar J.;Eibl, Guido
抗凋亡蛋白Bcl2家族蛋白在人类恶性肿瘤细胞的凋亡死亡中起重要作用。本研究的目的是阐明抗凋亡的Bcl2家族蛋白在胰腺癌(PACA)细胞存活中的作用机制。我们首先用Western印迹方法分析了抗细胞凋亡的Bcl2家族蛋白在6个PACA细胞系中的内源性表达和亚细胞定位。通过siRNA介导的蛋白表达下调来阐明Bcl2家族蛋白的功能作用。细胞死亡酶联免疫吸附试验和Hoechst 33258染色检测细胞凋亡率。结果表明，不同的PACA细胞系中抗凋亡蛋白Bcl2家族蛋白的表达存在差异。MCL-1基因敲除后，PARP裂解明显，并诱导细胞凋亡。下调Bcl2或Bclxl的作用要弱得多。同时下调Bclxl和Mcl-1可强烈诱导细胞凋亡，但同时下调Bclxl/Bcl2或Mcl-1/Bcl2无相加作用。同时下调Bclxl和Mcl-1的凋亡作用与Bax从胞浆移位到线粒体膜、细胞色素c释放和caspase激活有关。这些结果表明，Bclxl和Mcl-1在胰腺癌细胞的存活中起着重要作用。同时靶向Bclxl和Mcl-1可能是一种有趣的PACA治疗策略。
Anti-apoptotic Bcl-2 family proteins have been reported to play an important role in apoptotic cell death of human malignancies. The aim of this study was to delineate the mechanism of anti-apoptotic Bcl-2 family proteins in pancreatic cancer (PaCa) cell survival. We first analyzed the endogenous expression and subcellular localization of anti-apoptotic Bcl-2 family proteins in six PaCa cell lines by Western blot. To delineate the functional role of Bcl-2 family proteins, siRNA-mediated knock-down of protein expression was used. Apoptosis was measured by Cell Death ELISA and Hoechst 33258 staining. In the results, the expression of anti-apoptotic Bcl-2 family proteins varied between PaCa cell lines. Mcl-1 knock-down resulted in marked cleavage of PARP and induction of apoptosis. Down-regulation of Bcl-2 or Bcl-xL had a much weaker effect. Simultaneous knock-down of Bcl-xL and Mcl-1 strongly induced apoptosis, but simultaneous knock-down of Bcl-xL/Bcl-2 or Mcl-1/Bcl-2 had no additive effect. The apoptosis-inducing effect of simultaneous knock-down of Bcl-xL and Mcl-1 was associated with translocation of Bax from the cytosol to the mitochondrial membrane, cytochrome c release, and caspase activation. These results demonstrated that Bcl-xL and Mcl-1 play an important role in pancreatic cancer cell survival. Targeting both Bcl-xL and Mcl-1 may be intriguing therapeutic strategy in PaCa.
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影响因子：
2.9
作者：
Banerjee S;Choi M;Aboukameel A;Wang Z;Mohammad M;Chen J;Yang D;Sarkar FH;Mohammad RM
通讯作者：
Mohammad RM
影响因子：
2.9
作者：
Eibl, G;Reber, HA;Hines, OJ
通讯作者：
Hines, OJ
DOI：
10.1016/j.bbamcr.2011.05.003
发表时间：
2011-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Takahashi H;Chen MC;Pham H;Angst E;King JC;Park J;Brovman EY;Ishiguro H;Harris DM;Reber HA;Hines OJ;Gukovskaya AS;Go VL;Eibl G
通讯作者：
Eibl G
影响因子：
4.8
作者：
Du, Han;Wolf, Jacob;Kuwana, Tomomi
通讯作者：
Kuwana, Tomomi
影响因子：
4.3
作者：
Er, Ernine;Oliver, Lisa;Vallette, Francois M.
通讯作者：
Vallette, Francois M.