Oleanolic acid induces autophagic death in human gastric cancer cells in vitro and in vivo

• Published in: Cell biology international Vol. 40; no. 7; pp. 770 - 778
• Main Authors: Nie, Hao, Wang, Yu, Qin, Yong, Gong, Xing-Guo
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2016; Wiley Subscription Services, Inc
• Subjects: Animals; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; autophagic death; Autophagy; Autophagy - drug effects; Beclin-1 - genetics; Cell Line, Tumor; Female; Gastric cancer; Humans; in vivo; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred BALB C; Mice, Nude; mTOR; oleanolic acid; Oleanolic Acid - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Random Allocation; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; TOR Serine-Threonine Kinases - metabolism; Transfection; Xenograft Model Antitumor Assays; mTOR; autophagic death; in vivo; gastric cancer; oleanolic acid
• ISSN: 1065-6995; 1095-8355; 1095-8355
• DOI: 10.1002/cbin.10612

Oleanolic acid (OA), a plant‐derived pentacyclic terpenoid, is known to have hepatoprotective effects. In this study, we found that OA induced autophagic cell death in multiple human gastric cancer cell lines. Moreover, OA‐induced autophagy was shown for the first time in human gastric cancer cells, evidenced by the formation of GFP‐RFP‐LC3 puncta and autophagosomes. OA suppressed phospho‐mTOR through inhibition of the PI3 K/AKT and ERK/p38 MAPK signalling pathways and through activation of the AMPK signalling pathway. Furthermore, we found that OA‐induced cytotoxicity and autophagy could be blocked by the autophagy inhibitor 3‐methyladenine or via siRNA targeting Beclin‐1. Our in vivo research showed that OA delayed the formation of MGC‐803 tumours in an autophagy‐dependent manner. These results reveal a novel mechanism for OA in gastric cancer cells and suggest that OA could be a novel agent in the treatment of gastric cancer.