Title: NAD+ metabolism controls growth inhibition by HIF1 in normoxia and determines differential sensitivity of normal and cancer cells.
Authors: Luczak, Michal W; Krawic, Casey; Zhitkovich, Anatoly
Published In Cell Cycle, (2021 09)
Abstract: The hypoxia-induced transcription factor HIF1 inhibits cell growth in normoxia through poorly understood mechanisms. A constitutive upregulation of hypoxia response is associated with increased malignancy, indicating a loss of antiproliferative effects of HIF1 in cancer cells. To understand these differences, we examined the control of cell cycle in primary human cells with activated hypoxia response in normoxia. Activated HIF1 caused a global slowdown of cell cycle progression through G1, S and G2 phases leading to the loss of mitotic cells. Cell cycle inhibition required a prolonged HIF1 activation and was not associated with upregulation of p53 or the CDK inhibitors p16, p21 or p27. Growth inhibition by HIF1 was independent of its Asn803 hydroxylation or the presence of HIF2. Antiproliferative effects of hypoxia response were alleviated by inhibition of lactate dehydrogenase and, more effectively, by boosting cellular production of NAD+, which was decreased by HIF1 activation. In comparison to normal cells, various cancer lines showed several fold-higher expressions of NAMPT, which is a rate-limiting enzyme in the main biosynthetic pathway for NAD+. Inhibition of NAMPT activity in overexpressor cancer cells sensitized them to antigrowth effects of HIF1. Thus, metabolic changes in cancer cells, such as enhanced NAD+ production, create resistance to growth-inhibitory activity of HIF1 permitting manifestation of its tumor-promoting properties.Abbreviations: DMOG: dimethyloxalylglycine, DM-NOFD: dimethyl N-oxalyl-D-phenylalanine, NMN: β-nicotinamide mononucleotide.
PubMed ID: 34382917
MeSH Terms: A549 Cells; Adenocarcinoma, Bronchiolo-Alveolar/metabolism*; Adenocarcinoma, Bronchiolo-Alveolar/pathology; Amino Acids, Dicarboxylic/pharmacology; Basic Helix-Loop-Helix Transcription Factors/genetics; Basic Helix-Loop-Helix Transcription Factors/metabolism; Carcinoma, Non-Small-Cell Lung/metabolism*; Carcinoma, Non-Small-Cell Lung/pathology; Cell Cycle/drug effects; Cell Cycle/genetics; Cell Hypoxia/drug effects; Cell Hypoxia/genetics*; Cell Proliferation/drug effects; Cell Proliferation/genetics*; Cytokines/antagonists & inhibitors; Cytokines/metabolism; Fibroblasts/metabolism*; Gene Knockdown Techniques/methods; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*; L-Lactate Dehydrogenase/antagonists & inhibitors; L-Lactate Dehydrogenase/metabolism; Lung Neoplasms/metabolism*; Lung Neoplasms/pathology; NAD/metabolism*; Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors; Nicotinamide Phosphoribosyltransferase/metabolism; Signal Transduction/drug effects; Signal Transduction/genetics*; Transfection