Abstract
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.
Highlights
Hypoxia is a common state of cancer cells due to the lack of blood supply to the rapidly growing tumor
We first attempted to evaluate the extent of similarity in gene expression between cobalt and hypoxia treatment by constructing a list of hypoxia genes using hypoxia related gene sets that were published on the MSigDB database [19 by ten different studies [20,21,22,23,24,25,26,27,28,29]
Among the shared ‘hypoxia up’ genes we identified genes involved in carbohydrates metabolism, fructose, mannose, and glycolysis, (i.e., SLC2A1, known as GLUT1, PGM1, ALDOA, ALDOC, PFKFB3, PFKFB4, GYS1, GBE1, HK2, ENO2 and PGK1), genes involved in oxidoreductase activity (i.e., SCD, P4HA2, P4HA1, HMOX1 and EGLN1), in autophagy and tumor cell survival (i.e., BNIP3L) [32], in pH regulation (i.e., CA9) [33] in multidrug resistance (i.e., ABCB6) [34] in cell survival and proliferation (i.e., ADM, cyclin G2), in angiogenesis (i.e., EGLN1, ANG and ANGPTL4)
Summary
Hypoxia is a common state of cancer cells due to the lack of blood supply to the rapidly growing tumor.
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