Chemopreventive effect of resveratrol and apocynin on pancreatic carcinogenesis via modulation of nuclear phosphorylated GSK3β and ERK1/2
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Akihisa Kato1, Aya Naiki-Ito2, Takahiro Nakazawa1, Kazuki Hayashi1, Itaru Naitoh1, Katsuyuki Miyabe1, Shuya Shimizu1, Hiromu Kondo1, Yuji Nishi1, Michihiro Yoshida1, Shuichiro Umemura1, Yasuki Hori1, Toshio Mori4, Masahiro Tsutsumi5, Toshiya Kuno2, Shugo Suzuki2, Hiroyuki Kato2, Hirotaka Ohara3, Takashi Joh1, Satoru Takahashi2
1Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
2Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
3Department of Community-based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
4Radioisotope Research Center, Nara Medical University School of Medicine, Kashihara, Nara, Japan
5Department of Pathology, Saiseikai Chuwa Hospital, Sakurai, Nara, Japan
Aya Naiki-Ito, e-mail: [email protected]
Keywords: resveratrol, apocynin, pancreatic carcinogenesis, GSK3β, hamster
Received: June 16, 2015 Accepted: October 09, 2015 Published: October 19, 2015
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 GSK3βSer9 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 GSK3βSer9 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 GSK3βSer9 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.
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