E Platinum, a newly synthesized platinum compound, induces autophagy via inhibiting phosphorylation of mTOR in gastric carcinoma BGC-823 cells

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• 作者：Chen Hu^a ; ¹ ; Mei-Juan Zou^a ; ¹ ; Li Zhao^a ; Na Lu^a ; Ya-Jing Sun^a ; Shao-Hua Gou^b ; Tao Xi^a ; ^{Xi_tao18@sina.com.cn} ; Qing-Long Guo^a ; ^{anticancer_drug@yahoo.com.cn}
• 关键词：E Platinum ; Autophagy ; Cell growth ; mTOR ; Gastric carcinoma cells
• 刊名：Toxicology Letters
• 出版年：2012
• 期刊代码：49_03784274
• 类别：pha
• 出版时间：5 April, 2012
• 卷：210
• 期：1
• 页码：78-86
• 文件大小：1775 K

摘要

A tightly regulated catabolic process named autophagy involves the degradation of intracellular components via lysosomes. Here we investigate the antitumor effect of E Platinum, a newly synthesized derivative of oxaliplatin, in vivo and in vitro. E Platinum exhibits growth inhibition of various tumor cells in a dose-dependent manner, but the mechanism underlying it is unclear. Based on theory introducing autophagy, we preliminarily investigate whether autophagy could contribute to the antitumor activity of E Platinum. Our results showed that autophagy induced by 12.5 渭M E Platinum in gastric carcinoma BGC-823 cells was significantly characterized by the FITC-fluorescent microtubule associated protein 1 light chain 3 (MAP-LC3), lysosomal-rich/acidic compartments visualized with Lysotracker red (LTR-red) and an accumulation of numerous large autophagic vesicles within the cytoplasm, but not in the control cells. Meanwhile treatment of cells with 12.5 渭M E Platinum resulted in conversion of water soluble LC3 (LC3-I) to lipidated and autophagosome-associated form (LC3-II) as well as increasing expression of autophagy protein Beclin 1. Activation of predominant lysosomal aspartic protease, LAMP-1 and cathepsin D, was demonstrated. Moreover, RNA interference targeting Beclin 1, inhibition of autophagy by 3-methyladenine (3-MA) and chloroquine significantly suppressed the above process as well as the BGC-823 cells growth inhibition triggered by 12.5 渭M E Platinum. Studies of mechanism revealed that E Platinum suppressed activation of mTOR and p70S6K by decreasing phosphorylation of Akt, ERK1/2, JNK and p38 involved in mitogen-activated protein kinase signaling. We supported new evidences for E Platinum as a promising antitumor agent, involving with autophagy induction.