Identification of mTOR as a primary resistance factor of the IAP antagonist AT406 in hepatocellular carcinoma cells
| Autor: | Shao-Feng Wu, Pingguo Liu, Zhenyu Yin, Maochuan Zhen, Yilin Zhao, Fuqiang Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology Time Factors Apoptosis Acetates inhibitor of apoptosis (IAP) proteins Inhibitor of Apoptosis Proteins 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Medicine Cytotoxic T cell Protein Stability Triazines TOR Serine-Threonine Kinases Liver Neoplasms Imidazoles Ribosomal Protein S6 Kinases 70-kDa Hep G2 Cells Azocines XIAP Tumor Burden Oncology 030220 oncology & carcinogenesis Hepatocellular carcinoma mTOR Female RNA Interference OSI-027 Research Paper Signal Transduction medicine.medical_specialty Carcinoma Hepatocellular Ubiquitin-Protein Ligases Mice Nude P70-S6 Kinase 1 Antineoplastic Agents X-Linked Inhibitor of Apoptosis Protein Inhibitor of apoptosis Transfection 03 medical and health sciences Downregulation and upregulation AT406 Animals Humans Benzopyrans Benzhydryl Compounds neoplasms Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Dose-Response Relationship Drug business.industry Mcl-1 medicine.disease Xenograft Model Antitumor Assays digestive system diseases 030104 developmental biology Drug Resistance Neoplasm Mutation Proteolysis Cancer research Myeloid Cell Leukemia Sequence 1 Protein business |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Mao-Chuan Zhen 1, * , Fu-Qiang Wang 1, * , Shao-Feng Wu 1 , Yi-Lin Zhao 2 , Ping-Guo Liu 1 , Zhen-Yu Yin 1 1 Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, 361004, China 2 Department 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. |
| Databáze: | OpenAIRE |
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