Sestrin 2 suppresses cells proliferation through AMPK/mTORC1 pathway activation in colorectal cancer

• Published in: Oncotarget 2017-07, Vol.8 (30), p.49318-49328
• Main Authors: Wei, Jin-Lai, Fang, Min, Fu, Zhong-Xue, Zhang, Shou-Ru, Guo, Jin-Bao, Wang, Rong, Lv, Zhen-Bing, Xiong, Yong-Fu
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Models, Animal; Female; Gene Expression; Humans; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; Mitogen-Activated Protein Kinases - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Reactive Oxygen Species - metabolism; Research Paper; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.17595

Sestrin 2 is a conserved antioxidant protein that reduces reactive oxygen species (ROS) and inhibits mammalian target of rapamycin complex 1 (mTORC1). We previously showed that sestrin 2 is abnormally decreased in colorectal cancer (CRC). To elucidate the molecular mechanism behind the potential contribution of sestrin 2 to CRC, we used a lentiviral expression vector system to determine the effects of sestrin 2 overexpression on human CRC cells. We found that sestrin 2 overexpression decreased ROS production, inhibited cell growth, and stimulated apoptosis in two CRC cell lines. In parallel, expression of the proliferation marker PCNA was decreased, proapoptotic caspase 3, 7, and 9 levels were increased, and expression of the anti-apoptotic protein survivin was reduced. Sestrin 2 overexpression also activated the adenosine monophosphate-activated protein kinase (AMPK) pathway, and suppressed mTORC1 signaling. Treating CRC cells with compound C, an AMPK inhibitor, reversed or attenuated changes in proliferation, apoptosis, and signaling proteins of the AMPK/mTORC1 axis. In a xenograft mouse model, CRC growth was attenuated by sestrin 2 overexpression. These results suggest that sestrin 2 suppresses CRC cell growth through activation of the AMPK/mTORC1 pathway and induction of apoptosis, and could be a novel pharmacological target for the treatment of CRC.