title: 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.affiliation: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuramitsu
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tokuda
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Byron
authors.initials: B
authors.lastname: Baron
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Kitagawa
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Akada
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Science, Kyusyu University, Fukuokashi, Fukuoka, Japan.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Maehara
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Science, Kyusyu University, Fukuokashi, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan; Centre of Clinical Laboratories in Tokuyama Medical Association Hospital, Shunan, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakamura
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D016895:Culture Media, Serum-Free; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D059748:Proteolysis; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D016895:Culture Media, Serum-Free; D003841:Deoxycytidine; D011065:Poly(ADP-ribose) Polymerases; D000093542:Gemcitabine