oxalylglycine and Carcinoma--Non-Small-Cell-Lung

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

Topics: A549 Cells; Adenocarcinoma, Bronchiolo-Alveolar; Amino Acids, Dicarboxylic; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Hypoxia; Cell Proliferation; Cytokines; Fibroblasts; Gene Knockdown Techniques; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; L-Lactate Dehydrogenase; Lung Neoplasms; NAD; Nicotinamide Phosphoribosyltransferase; Signal Transduction; Transfection