TY - JOUR
T1 - Gemcitabine induces poly (ADP-Ribose) polymerase-1 (PARP-1) degradation through autophagy in pancreatic cancer
AU - Wang, Yufeng
AU - Kuramitsu, Yasuhiro
AU - Tokuda, Kazuhiro
AU - Baron, Byron
AU - Kitagawa, Takao
AU - Akada, Junko
AU - Maehara, Shin Ichiro
AU - Maehara, Yoshihiko
AU - Nakamura, Kazuyuki
N1 - Publisher Copyright:
© 2014 Wang et al.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0109076
DO - 10.1371/journal.pone.0109076
M3 - Article
C2 - 25271986
AN - SCOPUS:84907487256
VL - 9
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 10
M1 - e109076
ER -