A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis

Abstract

We have investigated the role of HIF-1 in the cellular response to redox modulation via the inhibition of oxidative phosphorylation. We demonstrate that manipulation of redox in air, achieved by inhibiting cytochrome oxidase with cyanide, induces HIF-1 mediated transcription in wild-type CHO and HT1080 human tumour cells but not in CHO cells de®cient in the oxygen responsive, HIF-1a sub-unit of HIF-1. Hypoglycaemia attenuates cyanide-mediated transcription in nontransformed HIF-1 wild-type CHO cells but not the human tumour derived cell line. Cells lacking either HIF1a, or the second composite sub-unit of HIF-1, HIF-1b, were markedly more sensitive to the combined stress of perturbed redox and hypoglycaemia than wild-type cells. As such conditions together with hypoxia are prevalent in tumours, these data suggest that HIF-1 may have a protective role in adaptation to the tumour microenvironment. In support of this we demonstrate that HIF-1a de®cient cells are less tumorigenic than wild-type cells. They showed a reduced growth rate when grown as xenografts in nude mice. This was not related to vascular parameters that were identical to those found in HIF-1 wild-type tumours. The HIF-1 de®cient tumours lacked focal expression of Glut-1 in hypoxic tumour regions. Compromized glucose uptake and metabolic adaptation to the tumour micro-environment may form the basis of the reduced tumorigenecity associated with these cells.

The hypoxia-inducible factor-1α is a negative factor for tumor therapy

“…Thus, as shown by most published experimental tumor models, HIF-1b (Jiang et al, 1997;Maxwell et al, 1997;Griffiths et al, 2002;Ho¨pfl et al, 2002) as well as HIF-1a (Ryan et al, 1998Kung et al, 2000;Ho¨pfl et al, 2002;Williams et al, 2002) are positive factors for solid tumor growth. However, in one embryonic stem cell tumor model, HIF-1a-deficient (HIF-1a À/À ) tumors have been shown to grow faster when compared with HIF-1a wildtype (HIF-1a +/+ ) tumors, apparently because of an increased rate of p53-dependent apoptosis in the HIF1a +/+ cells (Carmeliet et al, 1998).…”

Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells

“…Cells were maintained in hypoxic or standard atmospheric conditions and drugs administered for 16 h. Media were replaced and cells incubated under normoxia for 6 days before SRB assay as previously described (Vichai and Kirtikara, 2006), and the concentration that reduced growth by 50% (IC 50 ) was determined. Clonogenicity after a 16 h drug exposure was determined as previously described (Williams et al, 2002). IC 50 was the concentration resulting in a surviving fraction of 0.5 compared with untreated cells.…”

Differential cellular responses to exogenous DNA in mammalian cells and its effect on oligonucleotide-directed gene modification

“…[13][14][15] However, the story is far more complicated since CHO-K1 cells, which are considered to be tumorigenic, showed incomparably higher cellular response to dsDNA than HEK293 and melanoma cells. 16,17 It is possible that a high level of response to exogenous dsDNA in CHO-K1 cells could be due to species difference since rodent cells are known to express lower levels of many repair factors in the baseline state than human cell lines.…”