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Carcinogenic Nickel Induces Genes Involved with Hypoxic Stress¹

Nelson Institute of Environmental Medicine, and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016 [K. S., M. C.]; Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [M. B.]; and Department of Biology, Center for Molecular Genetics, University of California, San Diego, La Jolla, California 92093-0366 [H. R., R. J.]

Carcinogenic nickel compounds alter the program of gene expression in normal cells and induce a pattern of gene expression similar to that found in nickel-induced cancers. Here we have demonstrated that nickel exposure induced hypoxic signaling pathways by inducing hypoxia-inducible transcription factor-1 (HIF-1), which mediated the induction of genes required by cells to survive hypoxia. We also show that a new gene, Cap43, is dependent upon HIF-1 because only HIF-1-proficient cells induced Cap43 when exposed to either hypoxia or nickel. We also show that glyceraldehyde-3-phosphate dehydrogenase, a gene induced by hypoxia through HIF-1, was similar to Cap43 in that it required HIF-1-proficient cells to be induced by either nickel or hypoxia. These data demonstrate that nickel exposure turns on signaling for hypoxic stress, which may be important in its carcinogenesis.

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