Targeting PP2A activates AMPK signaling to inhibit colorectal cancer cells
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Cuiping Dai1, Xuning Zhang2,*, Da Xie3, Peipei Tang2, Chunmei Li2, Yi Zuo4, Baofei Jiang5 and Caiping Xue2
1Faculty of Health, Jiangsu Food and Pharmaceutical Science College, Huaian, China
2Huaian Key Laboratory Of Gastrointestinal Cancer, Jiangsu College of Nursing, Huaian, China
3Oncology Department, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
4Department of Medicine, Xinglin College, Nantong University, Nantong, China
5Gastrointestinal Surgery, The First People’s Hospital of Huaian City, Huaian, China
Caiping Xue, email: [email protected]; [email protected]
Baofei Jiang, email: [email protected]
Keywords: protein phosphatase 2A (PP2A); LB-100; colorectal cancer (CRC); AMP-activated protein kinase (AMPK) and mTOR
Received: August 01, 2017 Accepted: August 24, 2017 Published: September 28, 2017
LB-100 is a novel PP2A inhibitor. Its activity in human colorectal cancer (CRC) cells was tested. The in vitro studies demonstrated that LB-100 inhibited survival and proliferation of both established CRC cells (HCT-116 and HT-29 lines) and primary human colon cancer cells. Further, LB-100 activated apoptosis and induced G1-S cell cycle arrest in CRC cells. LB-100 inhibited PP2A activity and activated AMPK signaling in CRC cells. AMPKα1 dominant negative mutation, shRNA-mediated knockdown or complete knockout (by CRISPR/Cas9 method) largely attenuated LB-100-induced AMPK activation and HCT-116 cytotoxicity. Notably, microRNA-17-92-mediated silence of PP2A (regulatory B subunit) also activated AMPK and induced HCT-116 cell death. Such effects were again largely attenuated by AMPKα mutation, silence or complete knockout. In vivo studies showed that intraperitoneal injection of LB-100 inhibited HCT-116 xenograft growth in nude mice. Its anti-tumor activity was largely compromised against HCT-116 tumors-derived from AMPKα1-knockout cells. We conclude that targeting PP2A by LB-100 and microRNA-17-92 activates AMPK signaling to inhibit CRC cells.
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