title: Simultaneous knock-down of Bcl-xL and Mcl-1 induces apoptosis through Bax activation in pancreatic cancer cells.
abstract: 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 an intriguing therapeutic strategy in PaCa.
authors: Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors: Hiroki
authors: H
authors: Takahashi
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors: Monica C
authors: MC
authors: Chen
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors: Hung
authors: H
authors: Pham
authors: Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Yoichi
authors: Y
authors: Matsuo
authors: Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors: Hideyuki
authors: H
authors: Ishiguro
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors: Howard A
authors: HA
authors: Reber
authors: Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Hiromitsu
authors: H
authors: Takeyama
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors: Oscar J
authors: OJ
authors: Hines
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address: Geibl@mednet.ucla.edu.
authors: Guido
authors: G
authors: Eibl
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003841:Deoxycytidine; D045304:Cytochromes c; D020169:Caspases; D000093542:Gemcitabine
keywords: Apoptosis; Bax; Bcl-xL; Mcl-1; Pancreatic cancer
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