Targeting PP2A activates AMPK signaling to inhibit colorectal cancer cells

Abstract

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.

Molecular pathway analysis indicates a distinct metabolic and immune phenotype in women with right-sided colon cancer

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Dynamic Phosphoproteomics Uncovers Signaling Pathways Modulated by Anti-oncogenic Sphingolipid Analogs

“…Cells were harvested every 5 min during the first hour of treatment with either 5 M SH-BC-893 (heavy label) or 50 M C2-ceramide (medium label) or 10 M LB-100 (medium label) or DMSO (light label). Drug concentrations used for treatments are based on previously published references (5,7,19). Cells were collected by pipetting 75 ml (25 ml per SILAC channel) of culture into 425 ml of Ϫ80°C precooled ethanol.…”