Cyclin D1 extensively reprograms metabolism to support biosynthetic pathways in hepatocytes.

Autor:	Wu H; Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA., Kren BT; Research Service, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA., Lane AN; Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, and Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA., Cassel TA; Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, and Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA., Higashi RM; Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, and Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA., Fan TWM; Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, and Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA., Scaria GS; Hematology and Oncology Division, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA., Shekels LL; Research Service, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA., Klein MA; Hematology and Oncology Division, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA., Albrecht JH; Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address: albre010@umn.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Dec; Vol. 299 (12), pp. 105407. Date of Electronic Publication: 2023 Oct 28.
DOI:	10.1016/j.jbc.2023.105407
Abstrakt:	Cell proliferation requires metabolic reprogramming to accommodate biosynthesis of new cell components, and similar alterations occur in cancer cells. However, the mechanisms linking the cell cycle machinery to metabolism are not well defined. Cyclin D1, along with its main partner cyclin-dependent kinase 4 (Cdk4), is a pivotal cell cycle regulator and driver oncogene that is overexpressed in many cancers. Here, we examine hepatocyte proliferation to define novel effects of cyclin D1 on biosynthetic metabolism. Metabolomic studies reveal that cyclin D1 broadly promotes biosynthetic pathways including glycolysis, the pentose phosphate pathway, and the purine and pyrimidine nucleotide synthesis in hepatocytes. Proteomic analyses demonstrate that overexpressed cyclin D1 binds to numerous metabolic enzymes including those involved in glycolysis and pyrimidine synthesis. In the glycolysis pathway, cyclin D1 activates aldolase and GAPDH, and these proteins are phosphorylated by cyclin D1/Cdk4 in vitro. De novo pyrimidine synthesis is particularly dependent on cyclin D1. Cyclin D1/Cdk4 phosphorylates the initial enzyme of this pathway, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and metabolomic analysis indicates that cyclin D1 depletion markedly reduces the activity of this enzyme. Pharmacologic inhibition of Cdk4 along with the downstream pyrimidine synthesis enzyme dihydroorotate dehydrogenase synergistically inhibits proliferation and survival of hepatocellular carcinoma cells. These studies demonstrate that cyclin D1 promotes a broad network of biosynthetic pathways in hepatocytes, and this model may provide insights into potential metabolic vulnerabilities in cancer cells. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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