2. Academic Validation
  3. Inhibition of CDK9 exhibits anticancer activity in hepatocellular carcinoma cells via targeting ribonucleotide reductase

Inhibition of CDK9 exhibits anticancer activity in hepatocellular carcinoma cells via targeting ribonucleotide reductase

  • Toxicol Appl Pharmacol. 2023 May 26;116568. doi: 10.1016/j.taap.2023.116568.
Jiunn-Chang Lin 1,  Tsang-Pai Liu 1,  Yan-Bin Chen 2,  Tun-Sung Huang 3,  Tung-Ying Chen 4,  Pei-Ming Yang 5
Affiliations

Affiliations

  • 1 Department of Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan; MacKay Junior College of Medicine, Nursing, and Management, New Taipei City 11260, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; Liver Medical Center, MacKay Memorial Hospital, Taipei 10449, Taiwan; Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.
  • 2 Department of Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan.
  • 3 Department of Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; Liver Medical Center, MacKay Memorial Hospital, Taipei 10449, Taiwan.
  • 4 Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; Department of Pathology, MacKay Memorial Hospital, Taipei 10449, Taiwan.
  • 5 Liver Medical Center, MacKay Memorial Hospital, Taipei 10449, Taiwan; Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; TMU and Affiliated Hospitals Pancreatic Cancer Groups, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: yangpm@tmu.edu.tw.
PMID: 37245555 DOI: 10.1016/j.taap.2023.116568
Abstract

Cyclin-dependent kinase 9 (CDK9) inhibitors are a novel category of Anticancer treatment for cancers. However, their effects on hepatocellular carcinoma (HCC) are rarely investigated. Human ribonucleotide reductase (RR, which consists of RRM1 and RRM2 subunits) catalyzes the conversion of ribonucleoside diphosphate into 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools, which play essential roles in DNA synthesis and DNA repair. In this study, we identified that CDK9 protein expression in adjacent non-tumor tissues predicted HCC patients' overall and progression-free survivals. The Anticancer activity of a CDK9-selective inhibitor, LDC000067, on HCC cells was positively associated with its ability to inhibit the expression of RRM1 and RRM2. LDC000067 downregulated RRM1 and RRM2 expression through post-transcriptional pathway. Specifically, LDC000067 triggered RRM2 protein degradation via multiple pathways, including proteasome-, lysosome-, and calcium-dependent pathways. Furthermore, CDK9 positively correlates with RRM1 or RRM2 expression in HCC patients, and the expressions of these three genes were associated with the higher infiltration of immune cells in HCC. Taken together, this study identified the prognostic relevance of CDK9 in HCC and the molecular mechanism for the Anticancer effect of CDK9 inhibitors on HCC.

Keywords

Cyclin-dependent kinase 9; Hepatocellular carcinoma; Protein degradation; Ribonucleotide reductase.

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