Gemcitabine Induces Poly (ADP-Ribose) Polymerase-1 (PARP-1) Degradation through Autophagy in Pancreatic Cancer |
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| Authors: | Yufeng Wang Yasuhiro Kuramitsu Kazuhiro Tokuda Byron Baron Takao Kitagawa Junko Akada Shin-ichiro Maehara Yoshihiko Maehara Kazuyuki Nakamura |
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| Institution: | 1. Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.; 2. Department of Surgery and Science, Graduate School of Medical Science, Kyusyu University, Fukuokashi, Fukuoka, Japan.; 3. Centre of Clinical Laboratories in Tokuyama Medical Association Hospital, Shunan, Japan.; Johns Hopkins University, United States of America, |
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| 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. |
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