Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity. Issue 8 (20th August 2015)

• Record Type: Journal Article
• Authors: Wang, Wei-jia; Wang, Yuan; Hou, Pei-pei; Li, Feng-wei; Zhou, Bo; Chen, Hang-zi; Bian, Xue-li; Cai, Qi-xu; Xing, Yong-zhen; He, Jian-ping; Zhang, Hongkui; Huang, Pei-qiang; Lin, Tianwei; Wu, Qiao
• Is Part Of: Chemistry & biology. Volume 22:Issue 8(2015)
• Page Start: 1040
• Page End: 1051
• Publication Date: 2015-08-20
• Subjects: Biochemistry -- Periodicals; 540
• DOI: 10.1016/j.chembiol.2015.06.023
• Languages: English
• ISSNs: 1074-5521

Abstract

Summary: Apoptotic resistance is becoming a significant obstacle for cancer therapy as the majority of treatment takes the route of apoptotic induction. It is of great importance to develop an alternative strategy to induce cancer cell death. We previously reported that autophagic cell death mediated by nuclear receptor TR3 and driven by a chemical agonist, 1-(3, 4, 5-trihydroxyphenyl)nonan-1-one (THPN), is highly effective in the therapy of melanoma but not any other cancer types. Here, we discovered that the insensitivity of cancer cells to THPN originated from a high cellular Akt2 activity. Akt2 phosphorylation interferes with TR3 export to cytoplasm and targeting to mitochondria, which lead to the autophagic induction. Therefore, the TR3-mediated autophagy could be effectively induced in the otherwise insensitive cells by downregulating Akt2 activity. Highly effective antineoplastic compounds are developed through optimizing the structure of THPN. This study implicates a general strategy for cancer therapy by the induction of autophagic cell death. Graphical Abstract: Highlights: High Akt2 activity abolishes THPN-driven autophagic cell death Akt2 phosphorylates TR3 to block THPN-induced TR3 mitochondrial targeting An Akt2 inhibitor and THPN show synergy in inhibiting tumorigenesis Highly effective anti-tumor compounds are developed by optimizing the THPN structure Abstract : Wang et al. provide insight into the mechanism of Akt2-related resistance to autophagy, and demonstrate a new avenue to broaden the application of chemical compound THPN with Akt inhibitor to treat many types of cancers by induction of autophagic cell death.