Hypoxia-inducible transcription factor-1α promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway

Abstract

Background: Hypoxia-inducible transcription factor-1α (HIF-1α), which plays an important role in controlling the hypoxia-induced glycolysis pathway, is a "master" gene in the tissue hypoxia response during tumor development. However, its role in the apoptosis of non-small cell lung cancer remains unknown. Here, we have studied the effects of HIF-1α on apoptosis by modulating HIF-1α gene expression in A549 cells through both siRNA knock-down and over-expression.

Gene regulation in the adaptive process to hypoxia in lung epithelial cells

“…In a second hypothesis, HIF may play a role through the upregulation of glycolytic pathway. In A549 cells, knocking down HIF-1␣ inhibited glycolysis, increased the pH of the culture medium, and protected the cells from hypoxia-induced apoptosis (30). These studies suggest a primordial role of HIF in hypoxia-induced apoptosis and underscore the possibility that HIF acts through several pathways.…”

“…HK-I is the predominant isoform in human alveolar epithelial cells A549 under normoxic conditions. However, the hypoxic regulation of HK-I remains under debate since Riddle and coworkers (44) reported that this isoform was not regulated by hypoxia, whereas a recent paper by Luo et al (30) showed that similar experimental hypoxic conditions increased HK-I mRNA levels. HK-II is less expressed in normoxia, but its mRNA expression as well as protein expression and enzymatic activity are dramatically induced by hypoxia (44).…”

“…The mechanism of hypoxic induction of HK-II is quite similar to that described for GAPDH: it is a transcriptionally mediated mechanism, directly related to O 2 deprivation. HK genes contain several HRE, and gene activation is inhibited by HIF-1␣-siRNA, suggesting that their upregulation involves an HIF-dependent pathway (30).…”

Cited2, a Transcriptional Modulator Protein, Regulates Metabolism in Murine Embryonic Stem Cells

“…The role of p300 in ESC metabolism remains elusive. By monitoring glucose consumption and extracellular lactate production, we found that undifferentiated Cited2 ⌬/Ϫ ESCs metabolize ϳ20% more glucose via aerobic glycolysis than WT counterparts, with a concomitant regulation of glycolysis-associated genes, such as HK1 and PFK1-L. HK1 is a target gene of Oct4 and HIF-1 (41,50), two transcription factors previously shown to be modulated by Cited2 (8,22). A ChIP assay indicated that Cited2 is recruited to the HK1 gene promoter, further supporting the direct role of Cited2 in coordinating HK1 expression and glucose metabolism.…”

Review: Implications of In Vitro Research on the Effect of Radiotherapy and Chemotherapy Under Hypoxic Conditions

“…However, cells can also lower their level of energy production, and if so, glucose consumption and acidosis will not change rapidly. Indeed, HIF-1 not only stimulates glycolysis [71], it also suppresses mitochondrial function and oxygen consumption by directly transactivating the gene encoding pyruvate dehydrogenase kinase (PDK-1). PDK-1 inactivates pyruvate dehydrogenase, an enzyme of the Krebs cycle [72,73].…”