Triptolide has anticancer and chemosensitization effects by down-regulating Akt activation through the MDM2/REST pathway in human breast cancer.

Jing Xiong,Sheng Zhou,Zhiling Qu,Qin Yang,Yu Wang,Tiefen Su,Jiansha Li

doi:10.18632/oncotarget.8207

Abstract

Triptolide has been shown to exhibit anticancer activity. However, its mechanism of action is not clearly defined. Herein we report a novel signaling pathway, MDM2/Akt, is involved in the anticancer mechanism of triptolide. We observed that triptolide inhibits MDM2 expression in human breast cancer cells with either wild-type or mutant p53. This MDM2 inhibition resulted in decreased Akt activation. More specifically, triptolide interfered with the interaction between MDM2 and the transcription factor REST to increase expression of the regulatory subunit of PI3-kinase p85 and consequently inhibit Akt activation. We further showed that, regardless of p53 status, triptolide inhibited proliferation, induced apoptosis, and caused G1 phase cell cycle arrest. Triptolide also enhanced the cytotoxic effect of doxorubicin. MDM2 inhibition plays a causative role in these effects. The inhibitory effect of triptolide on MDM2-mediated Akt activation was eliminated with MDM2 overexpression. MDM2-overexpressing tumor cells, in turn, were less susceptible to the anticancer and chemosensitization effects of triptolide than control cells. Triptolide also exhibited anticancer and chemosensitization effects in nude mouse xenograft model. When it was administered to tumor-bearing nude mice, triptolide inhibited tumor growth and enhanced the antitumor effects of doxorubicin. In summary, triptolide has anticancer and chemosensitization effects by down-regulating Akt activation through the MDM2/REST pathway in human breast cancer. Our study helps to elucidate the p53-independent regulatory function of MDM2 in Akt signaling, offering a novel view of the mechanism by which triptolide functions as an anticancer agent.

Highlights

The mouse double minute 2 (MDM2) protein is a multifunctional oncoprotein that has been suggested to play both p53-dependent and -independent roles in oncogenesis
Chromatin immunoprecipitation (CHIP) assay results demonstrated that triptolide treatment enhanced localization of repressor element-1 silencing transcription factor (REST) on the p85 promoter (Figure 3D). These results indicate that triptolide interferes with the interaction between MDM2 and REST to increase expression of the regulatory subunit of PI3kinase p85 and inhibit Akt activation
Our observations suggest a novel signaling pathway, MDM2/Akt, is involved in the anticancer mechanism of triptolide

Summary

Introduction

The mouse double minute 2 (MDM2) protein is a multifunctional oncoprotein that has been suggested to play both p53-dependent and -independent roles in oncogenesis. MDM2 gained considerable attention following its identification as an important inhibitor of the tumor suppressor p53. The NH2 terminus of MDM2 protein binds to p53 and represses p53-mediated transcriptional activity [1], whereas its COOH terminus contains a RING finger domain that is an E3 ubiquitin ligase, promoting p53 ubiquitination and proteasomal degradation [2]. Increasing evidence suggests that MDM2 has activities independent of p53. In the presence or absence of functional p53, tumor cells which expressed high levels of MDM2 both show high invasive potential [3,4,5]. The interaction between MDM2 and p53 has been extensively investigated, the p53-independent oncogenic functions of MDM2 remains underexplored

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Conclusion