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Open AccessArticle

Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells

by Pei-Ming Yang 1,2,3,4, Li-Shan Lin 5 and Tsang-Pai Liu 1,5,6,7,8,*
1
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
2
PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
3
TMU Research Center of Cancer Translational Medicine, Taipei 11031, Taiwan
4
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
5
Department of Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan
6
Mackay Junior College of Medicine, Nursing and Management, New Taipei City 11260, Taiwan
7
Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan
8
Liver Medical Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(1), 117; https://doi.org/10.3390/biom10010117
Received: 30 October 2019 / Revised: 20 December 2019 / Accepted: 7 January 2020 / Published: 9 January 2020
(This article belongs to the Section Biochemistry)
The main curative treatments for hepatocellular carcinoma (HCC) are surgical resection and liver transplantation, which only benefits 15% to 25% of patients. In addition, HCC is highly refractory and resistant to cytotoxic chemotherapy. Although several multi-kinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, have been approved for treating advanced HCC, only a short increase of median overall survival in HCC patients was achieved. Therefore, there is an urgent need to design more effective strategies for advanced HCC patients. Human ribonucleotide reductase is responsible for the conversion of ribonucleoside diphosphate to 2′-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. In this study, mining the cancer genomics and proteomics data revealed that ribonucleotide reductase regulatory subunit M2 (RRM2) serves as a prognosis biomarker and a therapeutic target for HCC. The RNA sequencing (RNA-Seq) analysis and public microarray data mining found that RRM2 was a novel molecular target of sorafenib in HCC cells. In vitro experiments validated that sorafenib inhibits RRM2 expression in HCC cells, which is positively associated with the anticancer activity of sorafenib. Although both RRM2 knockdown and sorafenib induced autophagy in HCC cells, restoration of RRM2 expression did not rescue HCC cells from sorafenib-induced autophagy and growth inhibition. However, long-term colony formation assay indicated that RRM2 overexpression partially rescues HCC cells from the cytotoxicity of sorafenib. Therefore, this study identifies that RRM2 is a novel target of sorafenib, partially contributing to its anticancer activity in HCC cells. View Full-Text
Keywords: autophagy; hepatocellular carcinoma; ribonucleotide reductase; sorafenib autophagy; hepatocellular carcinoma; ribonucleotide reductase; sorafenib
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Yang, P.-M.; Lin, L.-S.; Liu, T.-P. Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells. Biomolecules 2020, 10, 117.

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