期刊论文详细信息
World Journal of Surgical Oncology
pERK1/2 silencing sensitizes pancreatic cancer BXPC-3 cell to gemcitabine-induced apoptosis via regulating Bax and Bcl-2 expression
Dong Chen1  Guangzhen Ni2  Zimin Liu1  Fengyun Hao2  Xueguang Dong3  Xingjiao Lu4  Min Wang3 
[1] Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China;Department of Clinical Laboratory, People’s Hospital of Weifang, Weifang, Shangdong, China;Department of Clinical Laboratory, People’s Hospital of Laiwu, Laiwu, Shangdong, China;Department of Internal Neurology, People’s Hospital of Zhangqiu, ZhangQiu, Shangdong, China
关键词: Gemcitabine;    Bax;    Bcl-2;    ERK1/2;    Pancreatic cancer;   
Others  :  1131010
DOI  :  10.1186/s12957-015-0451-7
 received in 2014-07-03, accepted in 2015-01-08,  发布年份 2015
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【 摘 要 】

Background

Our previous study has demonstrated that knockdown of activated ERK1/2(pERK1/2) sensitizes pancreatic cancer cells to chemotherapeutic drug gemcitabine (Gem) treatment. However, the details of this survival mechanism remain undefined. It has also shown that Bcl-2 confers resistance and Bax sensitizes to gemcitabine-induced apoptosis in pancreatic cancer cells. Furthermore, the extracellular signaling-regulated kinase (ERK) signaling pathway regulates Bcl-2/Bax expression ratio. We therefore tested the hypothesis that pancreatic cancer cells are resistant to gemcitabine and this resistance is due to activation of ERK1/2 and subsequent upregulation of Bcl-2 and downregulation of Bax.

Methods

Pancreatic cancer cell BXPC-3 was used in the study. The effect of pharmacological inhibition of ERK1/2 on resistance of pancreatic cancer cells to apoptosis induced by treatment with gemcitabine was analyzed. The following methods were utilized: TUNEL and ELISA were used to detect apoptosis. Western blot was used to detect the protein expression.

Results

Gemcitabine treatment enhanced the activity of ERK1/2 in the BXPC-3 cells. Inhibition of the ERK1/2 by PD98059 could downregulate Bcl-2 and upregulate Bax and was associated with restoration of sensitivity to gemcitabine in BXPC-3 cells. Depletion of endogenous Bcl-2 expression by specific small interfering RNA transfection significantly increased gemcitabine-induced cell apoptosis. Combined treatment with PD98059 and Bax siRNA transfection could decrease gemcitabine-induced ERK1/2 and Bax activation, which subsequently resulted in decreased apoptosis.

Conclusions

The upregulation of ERK1/2-dependent Bcl-2 and downregulation of ERK1/2-dependent Bax can protect human pancreatic cancer cells from gemcitabine-induced apoptosis. Targeting the ERK1/2-Bax/Bcl-2 pathway may in part lead to sensitization of pancreatic cancer to gemcitabine.

【 授权许可】

   
2015 Wang et al.; licensee BioMed Central.

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【 参考文献 】
  • [1]Squadroni M, Fazio N: Chemotherapy in pancreatic adenocarcinoma. Eur Rev Med Pharmacol Sci. 2010, 14:386-3894.
  • [2]Burris HA III, Moore MJ, Anderson J: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997, 15:2403-13.
  • [3]Rothenberg ML, Moore MJ, Cripps MC: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreatic cancer. Ann Oncol. 1996, 7:347-53.
  • [4]van Riel JMGH, van Groeningen CJ, Pinedo HM: Current chemotherapeutic possibilities in pancreaticobiliary cancer. Ann Oncol. 1999, 10:S157-61.
  • [5]Kroep JR, Pinedo CJ, van Groeningen CJ: Experimental drugs and drug combinations in pancreatic cancer. Ann Oncol. 1999, 10:S234-8.
  • [6]Arlt A, Gehrz A, Müerköster S, Vorndamm J, Kruse ML, Fölsch UR, et al.: Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene. 2003, 22:3243-51.
  • [7]Chadha KS, Khoury T, Yu J, Black JD, Gibbs JF, Kuvshinoff BW, Tan D, Brattain MG, Javle MM: Activated Akt and Erk expression and survival after surgery in pancreatic carcinoma. Ann Surg Oncol 2006, 13:933-9.
  • [8]Zheng C, Jiao X, Jiang Y, Sun S: ERK1/2 activity contributes to gemcitabine resistance in pancreatic cancer cells. J Int Med Res. 2013, 41:300-6.
  • [9]Hengartner MO: The biochemistry of apoptosis. Nature. 2010, 407:770-6.
  • [10]Lutz RJ: Role of the BH3 (bcl-2 homology 3) domain in the regulation of apoptosis and bcl-2-related proteins. Biochem Soc Trans. 2000, 28:51-6.
  • [11]Reed JC: bcl-2 family proteins. Oncogene 1998, 17:3225-36.
  • [12]Weinmann P, Bommert K, Mapara MY, Dörken B, Bargou RC: Overexpression of the death-promoting gene bax-alpha sensitizes human BL-41 Burkitt lymphoma cells for surface IgM-mediated apoptosis. Eur J Immunol. 2007, 27:2466-8.
  • [13]Okamoto K, Ocker M, Neureiter D, Dietze O, Zopf S, Hahn EG, Herold C: bcl-2-specific siRNAs restore gemcitabine sensitivity in human pancreatic cancer cells. J Cell Mol Med 2007, 11:349-61.
  • [14]Schniewind B, Christgen M, Kurdow R, Haye S, Kremer B, Kalthoff H, Ungefroren H: Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis. Int J Cancer. 2004, 109:182-8.
  • [15]Pirocanac EC, Nassirpour R, Yang M, Wang J, Nardin SR, Gu J, Fang B, Moossa AR, Hoffman RM, Bouvet M: bax-induction gene therapy of pancreatic cancer. J Surg Res 2002, 106:346-51.
  • [16]Seino S, Sunayama J, Matsuda KI, Sato A, Matsumoto Y, Nomiya T, Nemoto K, Yamashita H, Kayama T, Ando K, Kitanaka C: MEK-ERK-dependent multiple caspase activation by mitochondrial proapoptotic bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death. Cell Death Dis. 2002, 1:e60.
  • [17]Zhang W, Zhao L, Liu J, Du J, Wang Z, Ruan C, Dai K: Cisplatin induces platelet apoptosis through the ERK signaling pathway. Thromb Res. 2012, 130:81-91.
  • [18]Pan TL, Wang PW, Leu YL, Wu TH, Wu TS: Inhibitory effects of Scutellaria baicalensis extract on hepatic stellate cells through inducing G2/M cell cycle arrest and activating ERK-dependent apoptosis via bax and caspase pathway. J Ethnopharmacol. 2012, 139:829-37.
  • [19]Adams JM, Cory S: The bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007, 26:1324-37.
  • [20]Boucher MJ, Morisset J, Vachon PH, Reed JC, Lainé J, Rivard N: MEK/ERK signaling pathway regulates the expression of bcl-2, bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem. 2000, 79:355-69.
  • [21]Peyssonnaux C, Eyche’ne A: The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001, 93:53-62.
  • [22]Tang Y, Liu F, Zheng C, Sun S, Jiang Y: Knockdown of clusterin sensitizes pancreatic cancer cells to gemcitabine chemotherapy by ERK1/2 inactivation. J Exp Clin Cancer Res. 2012, 31:73. BioMed Central Full Text
  • [23]Sartorius UA, Krammer PH: Upregulation of bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. Int J Cancer. 2002, 97:584-92.
  • [24]Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ: bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia 1996, 10:456-9.
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