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Keren Cohen Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Uri Abadi Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Aleck Hercbergs Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA

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Paul J Davis Department of Medicine, Albany Medical College, Albany, New York, USA

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Martin Ellis Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Osnat Ashur-Fabian Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Multiple myeloma (MM) is a plasma cell malignancy in which involvement of the thyroid hormone-integrin αvβ3 pathway was shown, and pharmacologic inhibition of this pathway is a rational approach to disease management. A thyroid hormone derivative, tetraiodothyroacetic acid (tetrac), which inhibits l-thyroxine (T4) and 3,5,3′-triiodo-l-thyronine (T3) binding to αvβ3 integrin, was studied in five MM cell lines and primary bone marrow (BM) MM cells. Tetrac inhibited MM cell proliferation (absolute cell number/viability) and induced caspase-dependent apoptosis (annexin-V/PI and cell cycle). Activation of caspase-9 and caspase-3 was further demonstrated. Moreover, DNA damage markers, ataxia-telangiectasia-mutated (ATM) kinase, poly ADP-ribose polymerase (PARP-1) and histone γH2AX were induced by tetrac. The various tetrac-initiated effects were attenuated by Arg-Gly-Asp (RGD) peptide, suggesting integrin involvement. Primary BM mononuclear cells were harvested from MM patients (n = 39) at various disease stages. Tetrac-induced apoptosis (12/17 samples) and sensitized the cytotoxic action of bortezomib (6/9 samples). Lastly, expression of plasma membrane integrin αvβ3 was shown not only in the malignant plasma clone, but also in other cell populations within the BM samples (n = 25). Tetrac is anti-proliferative and pro-apoptotic in MM and cells may offer a therapeutic approach for this disease.

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Eilon Krashin Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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Barbara Silverman Israel National Cancer Registry, Ministry of Health, Gertner Institute, Sheba Medical Center, Tel Hashomer, Israel
School of Public Health, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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David M Steinberg Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel

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Daniel Yekutieli Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel

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Shmuel Giveon Clalit Health Services, Tel Aviv, Israel

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Offer Fabian Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel

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Aleck Hercbergs Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA

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Paul J Davis Department of Medicine, Albany Medical College, Albany, New York, USA

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Martin Ellis Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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Osnat Ashur-Fabian Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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Research on the association between thyroid hormone levels and cancer mortality remains limited and inconclusive. We determined the relation of thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels with mortality in overall cancer and specific tumor types. Thyroid hormone levels 1–5 years prior to cancer diagnosis, as well as multiple clinical and demographic parameters, were retrospectively collected for 10,325 Israeli cancer patients, diagnosed between 2000 and 2016. Patients treated with thyroid altering medications were excluded. Cancer diagnosis was determined via the Israel National Cancer Registry. Multivariate-adjusted Cox proportional hazards model was used to assess the hazard ratios (HRs) based on thyroid hormone function for cancer mortality. A total of 5265 patients died during the follow-up period (median of 4.4 years). TSH, FT4, and FT3 levels in the hypothyroid range were associated with increase in overall mortality (adjusted HR 1.20, 1.74, 1.87, respectively). We further analyzed the association between TSH and mortality in 14 cancer subgroups. Specifically, TSH in both the hyperthyroid and hypothyroid range was associated with melanoma mortality (adjusted HR 2.20, 4.47, respectively). In conclusion, pre-diagnosis of thyroid dysfunction is associated with increased cancer mortality, a relation likely driven by specific cancer types. These findings suggest that thyroid hormones may potentially serve as prognostic markers in cancer.

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Yu-Tang Chin Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

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Po-Li Wei Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
Department of Surgery, College of Medicine; Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan

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Yih Ho School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

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André Wendindondé Nana Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan

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Chun A Changou Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Core Facility, Taipei Medical University, Taipei, Taiwan
Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan

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Yi-Ru Chen Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

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Yu-Chen SH Yang Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan

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Meng-Ti Hsieh Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

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Aleck Hercbergs Department of Radiation Oncology, The Cleveland Clinic, Cleveland, Ohio, USA

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Paul J Davis Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
Department of Medicine, Albany Medical College, Albany, New York, USA

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Ya-Jung Shih Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

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Hung-Yun Lin Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

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Thyroid hormone, l-thyroxine (T4), has been shown to promote ovarian cancer cell proliferation via a receptor on plasma membrane integrin αvβ3 and to induce the activation of ERK1/2 and expression of programmed death-ligand 1 (PD-L1) in cancer cells. In contrast, resveratrol binds to integrin αvβ3 at a discrete site and induces p53-dependent antiproliferation in malignant neoplastic cells. The mechanism of resveratrol action requires nuclear accumulation of inducible cyclooxygenase (COX)-2 and its complexation with phosphorylated ERK1/2. In this study, we examined the mechanism by which T4 impairs resveratrol-induced antiproliferation in human ovarian cancer cells and found that T4 inhibited resveratrol-induced nuclear accumulation of COX-2. Furthermore, T4 increased expression and cytoplasmic accumulation of PD-L1, which in turn acted to retain inducible COX-2 in the cytoplasm. Knockdown of PD-L1 by small hairpin RNA (shRNA) relieved the inhibitory effect of T4 on resveratrol-induced nuclear accumulation of COX-2- and COX-2/p53-dependent gene expression. Thus, T4 inhibits COX-2-dependent apoptosis in ovarian cancer cells by retaining inducible COX-2 with PD-L1 in the cytoplasm. These findings provide new insights into the antagonizing effect of T4 on resveratrol’s anticancer properties.

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André Wendindondé Nana PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan

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Yu-Tang Chin PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Chi-Yu Lin Center for Teeth Bank and Dental Stem Cell Technology and School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan

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Yih Ho School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

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James A Bennett Center for Immunology and Microbial Diseases, Albany Medical College, Albany, New York, USA

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Ya-Jung Shih Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Yi-Ru Chen Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Chun A Changou PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan
Integrated Laboratory, Center of Translational Medicine, Core Facility, Taipei Medical University, Taipei, Taiwan

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Jens Z Pedersen Department of Biology, University Tor Vergata, Rome, Italy

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Sandra Incerpi Department of Sciences, University Roma Tre, Rome, Italy

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Leroy F Liu Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Jacqueline Whang-Peng Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Earl Fu Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan

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Wen-Shan Li Laboratory of Chemical Biology and Medicinal Chemistry, Institute of Chemistry, Academia Sinica, Taipei, Taiwan
Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Taipei, Taiwan

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Shaker A Mousa Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA

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Hung-Yun Lin PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

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Paul J Davis Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
Department of Medicine, Albany Medical College, Albany, New York, USA

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The molecular pathogenesis of colorectal cancer encompasses the activation of several oncogenic signaling pathways that include the Wnt/β-catenin pathway and the overexpression of high mobility group protein A2 (HMGA2). Resveratrol – the polyphenolic phytoalexin – binds to integrin αvβ3 to induce apoptosis in cancer cells via cyclooxygenase 2 (COX-2) nuclear accumulation and p53-dependent apoptosis. Tetraiodothyroacetic acid (tetrac) is a de-aminated derivative of l-thyroxine (T4), which – in contrast to the parental hormone – impairs cancer cell proliferation. In the current study, we found that tetrac promoted resveratrol-induced anti-proliferation in colon cancer cell lines, in primary cultures of colon cancer cells, and in vivo. The mechanisms implicated in this action involved the downregulation of nuclear β-catenin and HMGA2, which are capable of compromising resveratrol-induced COX-2 nuclear translocation. Silencing of either β-catenin or HMGA2 promoted resveratrol-induced anti-proliferation and COX-2 nuclear accumulation which is essential for integrin αvβ3-mediated-resveratrol-induced apoptosis in cancer cells. Concurrently, tetrac enhanced nuclear abundance of chibby family member 1, the nuclear β-catenin antagonist, which may further compromise the nuclear β-catenin-dependent gene expression and proliferation. Taken together, these results suggest that tetrac targets β-catenin and HMGA2 to promote resveratrol-induced-anti-proliferation in colon cancers, highlighting its potential in anti-cancer combination therapy.

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