Abstract
ObjectiveTo measure clusterin expression in pancreatic cancer tissues and cell lines and to evaluate whether clusterin confers resistance to gmcitabine in pancreatic cancer cells.MethodsImmunohistochemistry 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.ResultsPancreatic 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.ConclusionOur 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.
Highlights
Pancreatic cancer is resistant to almost all cytotoxic drugs
Expression of clusterin in pancreatic cancer tissues samples Clusterin protein immunoreactivity was detected both in matched backgrounds and pancreatic cancer cells
Of the 50 pancreatic cancer tissues, 26 (52%)exhibited clusterin overexpression in cancer cells, 4(8%) exhibited clusterin weak expression in cancer cells(Figure 1.A-C), and no clusterin staining was shown in 20 pancreatic cancertissues
Summary
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, 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]. Pancreatic cancer is resistant to almost all cytotoxic drugs. 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]. 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]. Clusterin has been regarded as a marker for cell death because its expression is up-regulated in various normal
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