title: Par-4 downregulation confers cisplatin resistance in pancreatic cancer cells via PI3K/Akt pathway-dependent EMT.
abstract: Cisplatin (CDDP) efficiency in pancreatic cancer therapy is limited due to development of drug resistance. However, the comprehensive mechanisms remain largely unclear. In this study, we first established a CDDP-resistant pancreatic cancer cell line-BXPC-3/CDDP from its parental cell line-BXPC-3. The results showed that CDDP resistance in BXPC-3/CDDP cells correlates with changes in cellular EMT phenotypes. Prostate apoptosis response-4 (Par-4) expression at both mRNA and protein levels were reduced in CDDP-resistant BXPC-3/CDDP cells compared with that in BXPC-3 cells. Ectopic expression of Par-4 reversed EMT and CDDP resistance in BXPC-3/CDDP cells. In BXPC-3 cells, knockdown of Par-4 expression induces EMT and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, Par-4 knockdown could significantly stimulate PI3K/Akt signaling in BXPC-3 cells. In vivo studies, xenograft BXPC-3 tumors were sensitive to CDDP treatment. Treatment with CDDP alone had little effect on the growth of Par-4 siRNA-transfected BXPC-3 tumors in nude mice and the survival rate compared with control. Inhibition of PI3K/Akt pathway using LY294002 reversed CDDP resistance in Par-4 siRNA-transfected BXPC-3 tumors. In conclusion, these results indicate that Par-4 downregulation confers CDDP resistance via PI3K/Akt pathway-dependent EMT in BXPC-3 cells. Therefore, Par-4 may be a potential target for overcoming CDDP resistance in pancreatic cancer.
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Tan
authors.forename: Yu
authors.initials: Y
authors.lastname: You
authors.forename: Tubin
authors.initials: T
authors.lastname: Xu
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Dingguo
authors.initials: D
authors.lastname: Wu
authors.forename: Hao
authors.initials: H
authors.lastname: Deng
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Bie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C101296:prostate apoptosis response-4 protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: CDDP, Cisplatin; EMT, Epithelial to mesenchymal transition; PI3K/Akt; Pancreatic cancer; Par-4, prostate apoptosis response-4