Targeting PP2A activates AMPK signaling to inhibit colorectal cancer cells.

Cuiping Dai,Da Xie,Chunmei Li,Xuning Zhang,Baofei Jiang,Caiping Xue,Yi Zuo,Peipei Tang

doi:10.18632/oncotarget.21336

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.

Highlights

Colorectal cancer (CRC) studies have been focusing on molecule-targeted therapy [1, 2] and exploring novel chemo-preventive agents [3,4,5,6]
In order to test the potential activity of LB-100 on human colorectal cancer (CRC) cells, the established HCT-116 HCC cells [5] were cultured in complete medium, and were treated with LB-100 at different concentrations
When analyzing signaling changes in tumor tissues, we demonstrate that LB-100 administration activated AMPK (AMPKα1/acetyl-CoA carboxylase (ACC) phosphorylations) in HCT-116 tumors (Figure 6D), which was followed by mTOR complex 1 (mTORC1) (p-p70S6K1) inhibition (Figure 6F)

Summary

Introduction

Colorectal cancer (CRC) studies have been focusing on molecule-targeted therapy [1, 2] and exploring novel chemo-preventive agents [3,4,5,6]. PP2A was traditionally viewed as a tumor suppressor [10, 11], recent cancer studies have indicated that PP2A inhibition could inhibit cancer cells via driving senescent cancer cells into mitosis or promoting cancer cell death and apoptosis [12, 13]. Several known PP2A inhibitors were shown to inhibit cancer cell proliferation and/or to induce cancer cell apoptosis [12, 13]. LB-100 is a novel small-molecule PP2A inhibitor [12,13,14]. Its potential activity in human CRC cells is tested here

Methods

Results

Discussion

Conclusion