Clusterin confers gmcitabine resistance in pancreatic cancer
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WORLD JOURNAL OF SURGICAL ONCOLOGY
RESEARCH
Open Access
Clusterin confers gmcitabine resistance in pancreatic cancer Qingfeng Chen1†, Zhengkun Wang1†, Kejun Zhang1†, Xiaoyi Liu1, Weihong Cao2, Lei Zhang3, Shuhua Zhang1, Bomin Yan1*, Yaoguang Wang4 and Chunping Xia4
Abstract Objective: To measure clusterin expression in pancreatic cancer tissues and cell lines and to evaluate whether clusterin confers resistance to gmcitabine in pancreatic cancer cells. Methods: Immunohistochemistry for clusterin was performed on 50 primary pancreatic cancer tissues and 25 matched backgrounds, and clusterin expression in 5 pancreatic cancer cell lines was quantified by Western blot and PT-PCR. The correlation between clusterin expression level and gmcitabine IC50 in pancreatic cancer cell lines was evaluated. The effect of an antisense oligonucleotide (ASO) against clusterin(OGX-011) on gmcitabine resistance was evaluated by MTT assays. Xenograft model was used to demonstrate tumor growth. Results: Pancreatic cancer tissues expressed significantly higher levels of clusterin than did normal pancreatic tissues (P < 0.01). Clusterin expression levels were correlated with gmcitabine resistance in pancreatic cancer cell lines, and OGX-011 significantly decreased BxPc-3 cells resistance to gmcitabine (P < 0.01). In vivo systemic administration of AS clusterin and gmcitabine significantly decreased the s.c. BxPC-3 tumor volume compared with mismatch control ODN plus gmcitabine. Conclusion: Our finding that clusterin expression was significantly higher in pancreatic cancer than in normal pancreatic tissues suggests that clusterin may confer gmcitabine resistance in pancreatic cancer cells.
Introduction Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gmcitabine appears to be the only clinically active drug but, because of pre-existing or acquired chemoresistance of most of the tumor cells, it failed to significantly improve the outcome of pancreatic carcinoma patients [1]. Clusterin, also known as testosterone-repressed prostate message-2 (TRPM-2), apolipoprotein J (ApoJ), sulfated glycoprotein-2 (SGP-2), and complement lysis inhibitor(CLI), was first isolated from ram rete testes fluid and plays important roles in various pathophysiological processes, such as tissue remodeling, lipid transport, complement regulation, and apoptosis [2]. Initially clusterin has been regarded as a marker for cell death because its expression is up-regulated in various normal
and malignant tissues undergoing apoptosis [3-5]. However, recent studies suggest a possible role for this gene in protecting cells from death, and consistently demonstrated that overexpression of clusterin closely correlates with the progression of various human malignancies [6-10]. More recent studies suggest that antisense oligonucleotide or interfering RNAs (siRNAs) to clusterin can enhance chemosensitivity in human cancer cells [11-15]. Taken together, these findings indicate that clusterin may play an important role in chemoresistance. To extend these o
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