Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells

Nickel is a human carcinogen that acts as a hypoxia mimic by activating the transcription factor HIF-1 alpha and hypoxia-like transcriptomic responses. Hypoxia and elevated HIF-1 alpha are typically associated with drug resistance in cancer cells, which is caused by increased drug efflux and other mechanisms. Here we examined the role of HIF-1 alpha in uptake of soluble Ni(II) and Ni(II)-induced cell fate outcomes using si/shRNA knockdowns and gene deletion models. We found that HIF-1 alpha had no effect on accumulation of Ni(II) in two transformed (H460, A549) and two normal human cell lines (IMR90, WI38). The loss of HIF-1 alpha also produced no significant impact on p53-dependent and p53-independent apoptotic responses or clonogenic survival of Ni(II)-treated transformed cells. In normal human cells, HIF-1 alpha enhanced the ability of Ni(II) to inhibit cell proliferation and cause a permanent growth arrest (senescence). Consistent with its growth-suppressive effects, HIF-1 alpha was important for upregulation of the cell cycle inhibitors p21 (CDKN1A) and p27 (CDKN1B). Irrespective of HIF-1 alpha status, Ni(II) strongly increased levels of MYC protein but did not change protein expression of the cell cycle promoting phosphatase CDC25A or the CDK inhibitor p16. Our findings indicate that HIF-1 alpha limits propagation of Ni(II)-damaged normal cells, suggesting that it may act in a tumor suppressor-like manner during early stages of Ni(II) carcinogenesis. (C) 2017 Elsevier Inc. All rights reserved.