M4IDP, a zoledronic acid derivative, induces G1 arrest, apoptosis and autophagy in HCT116 colon carcinoma cells via blocking PI3K/Akt/mTOR pathway

Abstract

AimsThe aim of this work was to examine the antitumor effects and mechanisms of M4IDP, a zoledronic acid derivative, on human colorectal cancer (CRC) HCT116 cells. Main methodsThe effects of M4IDP on proliferation, cell cycle and ROS production were determined by CCK-8 and flow cytometry assays. Annexin-V-FITC/PI, Hoechst 33258, MDC staining assays and Ad-mCherry-GFP-LC3B fluorescence assay were performed to investigate apoptosis and autophagy. The effects of M4IDP on the induction of ER stress as well as the expression of cell cycle, apoptosis and autophagy-related proteins were analyzed by western blot assay. Key findingsM4IDP exhibited strong and sustained inhibitory effect on the growth of HCT116 cells. G1 arrest caused by M4IDP might be attributed to the enhancement of p27 and reduction of cyclin D1 expression. Proper-time treatment of M4IDP activated autophagy and promoted autophagic flux, while long-time treatment might inhibit the autophagic degradation and undermine the autophagy. M4IDP-induced apoptosis and autophagy were related to the ROS production and subsequent ER stress. M4IDP treatment increased the expression of PTEN, inhibited the phosphorylation of PDK1, Akt, mTOR, p70S6K, and increased the phosphorylation of GSK-3β and Bad, suggesting that the inhibition of PI3K/Akt/mTOR pathway might be involved in the antitumor activities of M4IDP. SignificanceOur study indicates the antitumor properties of M4IDP and its potential clinical use in CRC therapy by blocking PI3K/Akt/mTOR pathway. This study also provides a better understanding of the antitumor effects and the underlying mechanisms of bisphosphonates in the field of CRC therapy.