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

Cancer Chemother Pharmacol. 2008 Nov;62(6):1055-64. doi: 10.1007/s00280-008-0697-7. Epub 2008 Feb 23.

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis / drug effects*
  • Base Sequence
  • Cell Cycle / drug effects
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics*
  • Gene Knockdown Techniques*
  • Genetic Vectors / therapeutic use*
  • Humans
  • Inverted Repeat Sequences
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • RNA Interference*
  • RNA, Small Interfering / pharmacology
  • RNA, Small Interfering / therapeutic use*
  • Specific Pathogen-Free Organisms
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Deoxycytidine
  • gemcitabine