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Su Jung Oh
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Holger H H Erb
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Alfred Hobisch Division of Experimental Urology, Department of Urology, Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

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Frédéric R Santer
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Zoran Culig
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Antihormonal and chemotherapy are standard treatments for nonorgan-confined prostate cancer. The effectivity of these therapies is limited and the development of alternative approaches is necessary. In the present study, we report on the use of the multikinase inhibitor sorafenib in a panel of prostate cancer cell lines and their derivatives which mimic endocrine and chemotherapy resistance. 3H-thymidine incorporation assays revealed that sorafenib causes a dose-dependent inhibition of proliferation of all cell lines associated with downregulation of cyclin-dependent kinase 2 and cyclin D1 expression. Apoptosis was induced at 2 μM of sorafenib in androgen-sensitive cells, whereas a higher dose of the drug was needed in castration-resistant cell lines. Sorafenib stimulated apoptosis in prostate cancer cell lines through downregulation of myeloid cell leukemia-1 (MCL-1) expression and Akt phosphorylation. Although concentrations of sorafenib required for the antitumor effect in therapy-resistant sublines were higher than those needed in parental cells, the drug showed efficacy in cells which became resistant to bicalutamide and docetaxel respectively. Most interestingly, we show that sorafenib has an inhibitory effect on androgen receptor (AR) and prostate-specific antigen expression. In cells in which AR expression was downregulated by short interfering RNA, the treatment with sorafenib increased apoptosis in an additive manner. In summary, the results of the present study indicate that there is a potential to use sorafenib in prostate cancers as an adjuvant therapy option to current androgen ablation treatments, but also in progressed prostate cancers that become unresponsive to standard therapies.

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Young Shin Song Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea

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Seong-Keun Yoo Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea

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Hwan Hee Kim Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea

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Gyeongseo Jung Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea

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Ah-Reum Oh Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University College of Medicine, Incheon, Korea

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Ji-Young Cha Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University College of Medicine, Incheon, Korea

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Su-jin Kim Department of Surgery, Seoul National University College of Medicine, Seoul, Korea

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Sun Wook Cho Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

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Kyu Eun Lee Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea

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Jeong-Sun Seo Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea

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Young Joo Park Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea
Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea

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Synergistic effects of BRAF V600E and TERT promoter mutations on the poor clinical outcomes in papillary thyroid cancer (PTC) have been demonstrated. The potential mechanism of this phenomenon has been proposed: MAPK pathway activation by the BRAF V600E mutation may upregulate E-twenty six (ETS) transcription factors, increasing TERT expression by binding to the ETS-binding site generated by the TERT promoter mutation; however, it has not yet been fully proven. This article provides transcriptomic insights into the interaction between BRAF V600E and TERT promoter mutations mediated by ETS factors in PTC. RNA sequencing data on 266 PTCs from The Cancer Genome Atlas and 65 PTCs from our institute were analyzed for gene expression changes and related molecular pathways, and the results of transcriptomic analyses were validated by in vitro experiments. TERT mRNA expression was increased by the coexistence of BRAF V600E and TERT promoter mutations (fold change, 16.17; q-value = 7.35 × 10−12 vs no mutation). In the ETS family of transcription factors, ETV1, ETV4 and ETV5 were upregulated by the BRAF V600E /MAPK pathway activation. These BRAF V600E -induced ETS factors selectively bound to the mutant TERT promoter. The molecular pathways activated by BRAF V600E were further augmented by adding the TERT promoter mutation, and the pathways related to immune responses or adhesion molecules were upregulated by TERT expression. The mechanism of the synergistic effect between BRAF V600E and TERT promoter mutations on cancer invasiveness and progression in PTC may be explained by increased TERT expression, which may result from the BRAF-induced upregulation of several ETS transcription factors.

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