Autophagy is needed for the growth of pancreatic adenocarcinoma and has a cytoprotective effect against anticancer drugs

Eur J Cancer. 2014 May;50(7):1382-90. doi: 10.1016/j.ejca.2014.01.011. Epub 2014 Feb 3.

Abstract

Background and aim: Autophagy is a regulated process of degradation and recycling of cellular constituents. The role of autophagy in pancreatic cancer is still not clear. Some studies indicate that in pancreatic cancer autophagy exerts cytoprotective effects, whereas others suggest that autophagy positively contributes to cell death by enhancing cytotoxicity of anticancer drugs. The aim of this study was to investigate the role of autophagy in pancreatic cancer, and to provide insights into new strategies for treatment.

Materials and methods: Pancreatic cancer cell lines PANC-1 and BxPC-3 were treated with anticancer drugs (5-fluorouracil or gemcitabine) alone and in combination with autophagy inhibitors (chloroquine or wortmannin). Biopsy samples were retrieved from patients from pancreatic normal tissue and adenocarcinoma. Western blot of microtubule-associated protein 1 light chain 3 (LC3)-II was performed to investigate the degree of autophagy and cell proliferation was assessed by a crystal violet assay.

Results: Autophagy was active in PANC-1 cells under basal conditions. Autophagy was significantly induced in pancreatic ductal adenocarcinoma compared to healthy pancreatic tissue in patients. Inhibition of autophagy by chloroquine suppressed the growth of PANC-1 and BxPC-3. Autophagy was markedly increased after treatment with 5-fluorouracil or gemcitabine. Inhibition of autophagy by chloroquine potentiated the inhibition of cell proliferation of PANC-1 and BxPC-3 by 5-fluorouracil and gemcitabine.

Conclusions: Our results with pancreatic cancer cell lines and human pancreatic adenocarcinoma suggest that autophagy contributes to pancreatic cancer cell growth. Autophagy has a cytoprotective effect against 5-fluorouracil and gemcitabine in pancreatic cancer cells. Combination therapy of these anticancer drugs and chloroquine should be investigated.

Keywords: 5-Fluorouracil; Autophagy; BxPC-3; Chemotherapy; Chloroquine; Gemcitabine; LC3; PANC-1; Pancreatic cancer; Wortmannin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / metabolism
  • Adenocarcinoma* / pathology
  • Androstadienes / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chloroquine / pharmacology
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Fluorouracil / pharmacology
  • Gemcitabine
  • Humans
  • Microtubule-Associated Proteins / metabolism
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Wortmannin

Substances

  • Androstadienes
  • Antineoplastic Agents
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Protein Kinase Inhibitors
  • Deoxycytidine
  • Chloroquine
  • Fluorouracil
  • Wortmannin
  • Gemcitabine