Gemcitabine induces poly (ADP-ribose) polymerase-1 (PARP-1) degradation through autophagy in pancreatic cancer

PLoS One. 2014 Oct 1;9(10):e109076. doi: 10.1371/journal.pone.0109076. eCollection 2014.

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) and autophagy play increasingly important roles in DNA damage repair and cell death. Gemcitabine (GEM) remains the first-line chemotherapeutic drug for pancreatic cancer (PC). However, little is known about the relationship between PARP-1 expression and autophagy in response to GEM. Here we demonstrate that GEM induces DNA-damage response and degradation of mono-ADP ribosylated PARP-1 through the autophagy pathway in PC cells, which is rescued by inhibiting autophagy. Hypoxia and serum starvation inhibit autophagic activity due to abrogated GEM-induced mono-ADP-ribosylated PARP-1 degradation. Activation of extracellular regulated protein kinases (ERK) induced by serum starvation shows differences in intracellular localization as well as modulation of autophagy and PARP-1 degradation in GEM-sensitive KLM1 and -resistant KLM1-R cells. Our study has revealed a novel role of autophagy in PARP-1 degradation in response to GEM, and the different impacts of MEK/ERK signaling pathway on autophagy between GEM-sensitive and -resistant PC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology*
  • Autophagy / drug effects
  • Culture Media, Serum-Free
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Gemcitabine
  • Humans
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Proteolysis

Substances

  • Antimetabolites, Antineoplastic
  • Culture Media, Serum-Free
  • Deoxycytidine
  • Poly(ADP-ribose) Polymerases
  • Gemcitabine

Grants and funding

The work was supported by grant no. 24501352, www.jsps.go.jp/g-grantsinaid. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.