Inducing apoptosis and enhancing chemosensitivity to Gemcitabine via RNA interference targeting Mcl-1 gene in pancreatic carcinoma cell

• DOI: 10.1007/s00280-008-0697-7
• Publication Date: 2008-02-22T07:57:35Z
• Authors: San-Hua Wei; Ke Dong; Fang Lin; Xi Wang; Bin Li; Jian-jun Shen; Qing Zhang; Rui Wang; Hui-Zhong Zhang
• Keywords: Antimetabolites, Antineoplastic; 0303 health sciences; Base Sequence; Cell Cycle; Genetic Vectors; Inverted Repeat Sequences; Molecular Sequence Data; Down-Regulation; Mice, Nude; Apoptosis; Adenocarcinoma; Deoxycytidine; Neoplasm Proteins; 3. Good health; Pancreatic Neoplasms; Mice; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; Gene Knockdown Techniques; Animals; Humans; Myeloid Cell Leukemia Sequence 1 Protein

Resistance to chemotherapy is a major cause of treatment failure and poor prognosis in pancreatic carcinoma. Myeloid cell leukemia-1 (Mcl-1) is highly up-regulated in pancreatic carcinoma and is associated with the anti-apoptosis and the resistance to chemotherapy drugs. Suppression of Mcl-1 would be an approach to induce apoptosis and enhance the chemosensitivity.In this study, three pancreatic cancer cell lines (PANC-1, BxPC-3 and SW1900) stably expressing shRNAs targeting Mcl-1 gene were established and gene expression inhibition was assessed by Real-Time QPCR and Western blotting. The effects of Mcl-1 downregulation mediated by RNAi were explored in vitro and in vivo.We showed that the specific downregulation of Mcl-1 strikingly inhibited cell growth, colony formation, cell cycle arrest and induced apoptosis in pancreatic cancer cells in vitro, and markedly decreased the tumorigenicity in a mouse xenograft model. Moreover, knockdown of Mcl-1 significantly increased the chemosensitivity to Gemcitabine in pancreatic carcinoma cells.Our data suggests that the specific downregulation of Mcl-1 by RNAi is a promising approach to induce apoptosis and enhance the chemosensitivity for pancreatic carcinoma gene therapy.