Abstract
// Hanyang Liu 1, * , Jun Song 1, * , Yan Zhou 1 , Yu Gong 1 , Liang Cao 1 , Haojun Yang 1 and Liming Tang 1 1 Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People’s Hospital, Changzhou, China * Co-first authors and these authors contributed equally to this work Correspondence to: Liming Tang, email: halfmoonstar@foxmail.com Haojun Yang, email: yhjmr@163.com Keywords: methylxanthine derivatives; autophagy; PTEN; PI3K/Akt/mTOR; gastric cancer Received: August 31, 2017 Accepted: November 16, 2017 Published: January 02, 2018 ABSTRACT Methylxanthine derivatives, such as caffeine and theophylline, enhance cell apoptosis and autophagy, and reportedly induce PTEN and inhibit mammalian target of rapamycin (mTOR). This study investigated the impact of caffeine and theophylline on gastric cancer cell apoptosis and autophagy using a gastric cancer cell line (MGC-803) and a nude mouse model. Peritumoral and tumor tissues were collected from five patients diagnosed with gastric carcinoma who underwent laparoscopic radical gastrectomy in our hospital. Autophagy was suppressed in gastric cancer tumors as compared to peritumoral tissues. In vitro , both caffeine and theophylline effectively suppressed MGC-803 cell proliferation and migration, and induced autophagy. To assess PTEN involvement in caffeine- and theophylline-mediated gastric cancer cell death, we transiently transfected MGC-803 cells with siRNA targeting PTEN. PTEN knockdown impaired methylxanthine derivative-mediated inhibition of PI3K/Akt/mTOR signaling. In nude mice treated with caffeine or theophylline, MGC-803 cell tumors injected with siPTEN were larger than those injected with negative control siRNA. These results show that methylxanthine derivatives (caffeine and theophylline) effectively induce gastric cancer cell apoptosis and autophagy via PTEN activation and PI3K/Akt/mTOR pathway suppression, and strongly support use of methylxanthine derivatives as potential anticancer therapeutics.
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