Oncotarget

Research Papers:

Identification of mTOR as a primary resistance factor of the IAP antagonist AT406 in hepatocellular carcinoma cells

Mao-Chuan Zhen, Fu-Qiang Wang, Shao-Feng Wu, Yi-Lin Zhao, Ping-Guo Liu and Zhen-Yu Yin _

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Oncotarget. 2017; 8:9466-9475. https://doi.org/10.18632/oncotarget.14326

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Abstract

Mao-Chuan Zhen1,*, Fu-Qiang Wang1,*, Shao-Feng Wu1, Yi-Lin Zhao2, Ping-Guo Liu1, Zhen-Yu Yin1

1Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, 361004, China

2Department of Tumor Interventional Radiology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, 361004, China

*These authors contributed equally to this work

Correspondence to:

Zhen-Yu Yin, email: yinzyxmu@163.com

Ping-Guo Liu, email: liu_pingguo88@yeah.net

Keywords: inhibitor of apoptosis (IAP) proteins, AT406, Mcl-1, mTOR, OSI-027

Received: July 04, 2016     Accepted: December 15, 2016     Published: December 28, 2016

ABSTRACT

Dysregulation of inhibitor of apoptosis (IAP) proteins (IAPs) in hepatocellular carcinoma (HCC) is often associated with poor prognosis. Here we showed that AT406, an IAP antagonist, was cytotoxic and pro-apoptotic to both established (HepG2, SMMC-7721 lines) and primary HCC cells. Activation of mTOR could be a key resistance factor of AT406 in HCC cells. mTOR inhibition (by OSI-027), kinase-dead mutation or knockdown remarkably enhanced AT406-induced lethality in HCC cells. Reversely, forced-activation of mTOR by adding SC79 or exogenous expressing a constitutively active S6K1 (T389E) attenuated AT406-induced cytotoxicity against HCC cells. We showed that AT406 induced degradation of IAPs (cIAP-1 and XIAP), but didn’t affect another anti-apoptosis protein Mcl-1. Co-treatment of OSI-027 caused simultaneous Mcl-1 downregulation to overcome AT406’s resistance. Significantly, shRNA knockdown of Mcl-1 remarkably facilitated AT406-induced apoptosis in HCC cells. In vivo, AT406 oral administration suppressed HepG2 tumor growth in nude mice. Its activity was potentiated with co-administration of OSI-027. We conclude that mTOR could be a key resistance factor of AT406 in HCC cells.


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