HYPOXIA Will Ascorbate Ameliorate the Effects of Carcinogenic Metals?

Hypoxia-inducible transcription factor (HIF) activates the transcription of genes involved in processes such as angiogenesis or glycolysis, which mediate homeostatic responses aimed at restoring or adapting to a compromised oxygen supply but which are also implicated in cancer biology. HIF is degraded during normal oxygen exposure but accumulates during hypoxia because of a reduction in the oxygen-dependent activity of prolyl hydroxylases (which hydroxylate the HIF- subunit and thereby target it for degradation). During HIF hydroxylation, hydroxylase-bound iron(II) is converted to iron(III), leading to inactivation of the enzyme, which is reactivated when ascorbate reduces iron(III) back to iron(II). The carcinogenic metals nickel and cobalt promote HIF-1 accumulation even in the presence of oxygen through mechanisms that are unclear. Salnikow et al. found that nickel(II) and cobalt(II) slightly inhibited HIF- oxygen-dependent degradation domain (ODD, a target for hydroxylation)-dependent hydroxylase activity in vitro, but markedly increased the stability of an ODD-containing reporter expressed in human lung epithelial (lHAEo-) and renal carcinoma cells and the transcription of a reporter containing a HIF response element. Exposure to nickel(II) or cobalt(II) inhibited uptake of radiolabeled ascorbate into lHAEo- cells, leading to a decrease in intracellular ascorbate concentration. Exposure to 100 µM ascorbate (which restored intracellular ascorbate) reversed the effects of nickel(II) and cobalt(II) on HIF-reporter stability and HIF-dependent transcription and prevented an increase in concentration of an endogenous hypoxia-inducible protein. In contrast, iron exposure had little effect. Thus, the authors propose that ascorbate depletion constitutes a major mechanism whereby nickel and cobalt promote HIF accumulation and thereby a hypoxic stress response.

K. Salnikow, S. P. Donald, R. K. Bruick, A. Zhitkovich, J. M. Phang, K. S. Kasprzak, Depletion of intracellular ascorbate by the carcinogenic metals nickel and cobalt results in the induction of hypoxic stress. J. Biol. Chem. 279, 40337-40344 (2004). [Abstract] [Full Text]

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Responding to Hypoxia: Lessons From a Model Cell Line

K. A. Seta, Z. Spicer, Y. Yuan, G. Lu, and D. E. Millhorn (20 August 2002)
Sci. STKE 2002 (146), re11. [DOI: 10.1126/stke.2002.146.re11]
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