title: Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity.
abstract: 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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Wei-jia
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Pei-pei
authors.initials: PP
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Feng-wei
authors.initials: FW
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Hang-zi
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Xue-li
authors.initials: XL
authors.lastname: Bian
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Qi-xu
authors.initials: QX
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Yong-zhen
authors.initials: YZ
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China.
authors.forename: Jian-ping
authors.initials: JP
authors.lastname: He
authors.affiliation: Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian Province, P.R. China.
authors.forename: Hongkui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian Province, P.R. China.
authors.forename: Pei-qiang
authors.initials: PQ
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China. Electronic address: twlin@xmu.edu.cn.
authors.forename: Tianwei
authors.initials: T
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, P.R. China. Electronic address: qiaow@xmu.edu.cn.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists* / Q000378:metabolism; D011748:Pyrogallol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C587356:1-(3,4,5-trihydroxyphenyl)nonan-1-one; D000970:Antineoplastic Agents; D007659:Ketones; D011988:Receptors, Thyroid Hormone; D011748:Pyrogallol; D051057:Proto-Oncogene Proteins c-akt