title: Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway.
abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells.
authors.affiliation: Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
authors.forename: Hsiang-Cheng
authors.initials: HC
authors.lastname: Chi
authors.affiliation: Department of Life Sciences, National Central University, Taoyuan 333, Taiwan, Republic of China.
authors.forename: Shen-Liang
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Cheng
authors.affiliation: Division of Neurosurgery, Chang Gung Memorial Hospital Linkou and Chang Gung University, Taoyuan 333, Taiwan, Republic of China.
authors.forename: Tzu-Kang
authors.initials: TK
authors.lastname: Lin
authors.affiliation: Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
authors.forename: Chung-Ying
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan.|Department of General Surgery, Chang Gung Memorial Hospital Chiayi 613, Taiwan.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
authors.forename: Yang-Hsiang
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.|Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013963:Thyroid Hormones / Q000494:pharmacology*
chemical_list: D000072224:Bcl-2-Like Protein 11; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D053221:TNF-Related Apoptosis-Inducing Ligand; D013963:Thyroid Hormones; D004317:Doxorubicin; D002945:Cisplatin