Hypoxia-inducible factor 1 (HIF-1), the major
transcription factor specifically activated during
hypoxia, regulates genes involved in critical aspects of
cancer biology, including angiogenesis, cell proliferation, glycolysis and invasion. The HIF-1a subunit is stabilized by low
oxygen, genetic alteration and cobaltous
ions, and its over-expression correlates with drug resistance and increased
cancer mortality in various
cancer types, therefore representing an important anticancer target.
Zinc supplementation has been shown to counteract the hypoxic phenotype in
cancer cells, in vitro and in vivo, hence, understanding the molecular pathways modulated by
zinc under
hypoxia may provide the basis for reprogramming signalling pathways for anticancer
therapy. Here we performed genome-wide analyses of
colon cancer cells treated with combinations of
cobalt,
zinc and anticancer drug and evaluated the effect of
zinc on gene expression patterns. Using Principal Component Analysis we found that
zinc markedly reverted the
cobalt-induced changes of gene expression, with reactivation of the drug-induced transcription of pro-apoptotic genes. We conclude that the
hypoxia pathway is a potential therapeutic target addressed by
zinc that also influences
tumor cell response to anticancer drug.