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

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.

• Authors: Yufeng Wang, Yasuhiro Kuramitsu, Kazuhiro Tokuda, Byron Baron, Takao Kitagawa, Junko Akada, Shin-ichiro Maehara, Yoshihiko Maehara, Kazuyuki Nakamura
• Journal: PloS one (PLoS One) Vol. 9 Issue 10 Pg. e109076 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25271986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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