title: Chemopreventive effect of resveratrol and apocynin on pancreatic carcinogenesis via modulation of nuclear phosphorylated GSK3β and ERK1/2.
abstract: Despite progress in clinical cancer medicine in multiple fields, the prognosis of pancreatic cancer has remained dismal. Recently, chemopreventive strategies using phytochemicals have gained considerable attention as an alternative in the management of cancer. The present study aimed to evaluate the chemopreventive effects of resveratrol (RV) and apocynin (AC) in N-Nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamster. RV- and AC-treated hamsters showed significant reduction in the incidence of pancreatic cancer with a decrease in Ki-67 labeling index in dysplastic lesions. RV and AC suppressed cell proliferation of human and hamster pancreatic cancer cells by inhibiting the G1 phase of the cell cycle with cyclin D1 downregulation and inactivation of AKT-GSK3β and ERK1/2 signaling. Further, decreased levels of GSK3β(Ser9) and ERK1/2 phosphorylation and cyclin D1 expression in the nuclear fraction were observed in cells treated with RV or AC. Nuclear expression of phosphorylated GSK3β(Ser9) was also decreased in dysplastic lesions and adenocarcinomas of hamsters treated with RV or AC in vivo. These results suggest that RV and AC reduce phosphorylated GSK3β(Ser9) and ERK1/2 in the nucleus, resulting in inhibition of the AKT-GSK3β and ERK1/2 signaling pathways and cell cycle arrest in vitro and in vivo. Taken together, the present study indicates that RV and AC have potential as chemopreventive agents for pancreatic cancer.
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kato
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Naiki-Ito
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Naitoh
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Miyabe
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Shuya
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishi
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Umemura
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Radioisotope Research Center, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Pathology, Saiseikai Chuwa Hospital, Sakurai, Nara, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsutsumi
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Kuno
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Shugo
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Community-based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ohara
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008647:Mesocricetus; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D013267:Stilbenes; C056165:acetovanillone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000077185:Resveratrol
keywords: GSK3β; apocynin; hamster; pancreatic carcinogenesis; resveratrol