| Molecular Mechanisms of Transformation of C3H/10T1/2 C1 8 Mouse Embryo Cells and Diploid Human Fibroblasts by Carcinogenic Metal Compounds Environ Health Perspect Key words: morphological and anchorage-independent transformation, carcinogenic metal salts, prostaglandins, oncogenes
This paper was presented at the Second International Meeting on Molecular Mechanisms of Metal Toxicity and Carcinogenicity held 10-17 January 1993 in Madonna di Campiglio, Italy.
This work was supported by grant ES03341 from the National Institute of Environmental Health Sciences and by grant lRT367 from the Tobacco-related Disease Research Program of the State of California to JRL.
Address correspondence to Dr. J. R. Landolph, Departments of Microbiology, Pathology, and Molecular Pharmacology and Toxicology, P.O. Box 33800, 1441 Eastlake Avenue, University of Southern California, Comprehensive Cancer Center, Schools of Medicine and Pharmacy, Los Angeles, CA 90033-0800. Telephone 213 224-6526. Fax 213 224-6417.
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Carcinogenic arsenic, nickel, and chromium compounds induced morphological and neoplastic transformation but no mutation to ouabain resistance in 10T1/2 mouse embryo cells ; lead chromate also did not induce mutation to ouabain or 6-thioguanine resistance in Chinese hamster ovary cells. The mechanism of metal-induced morphological transformation was likely not due to the specific base substitution mutations measured in ouabain resistance mutation assays, and for lead chromate, likely not due to this type of base substitution mutation or to frameshift mutations. Preliminary data indicate increases in steady-state levels of c-myc RNA in arsenic-, nickel-, and chromium-transformed cell lines. We also showed that carcinogenic nickel, chromium, and arsenic compounds and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induced stable anchorage independence (AI) in diploid human fibroblasts (DHF) but no focus formation or immortality. Nickel subsulfide and lead chromate induced AI but not mutation to 6-thioguanine resistance. The mechanism of induction of AI by metal salts in DHF was likely not by the type of base substitution or frameshift mutations measured in these assays. MNNG induced AI, mutation to 6-thioguanine resistance, and mutation to ouabain resistance,and might induce AI by base substitution or frameshift mutations. Dexamethasone, aspirin, and salicylic acid inhibited nickel subsulfide, MNNG, and 12-O-tetradecanoylphorbol-13-acetate (TPA) -induced AI in DHF, suggesting that arachidonic acid metabolism and oxygen radical generation play a role in induction of AI. We propose that nickel compounds stimulate arachidonic acid metabolism, consequent oxygen radical generation, and oxygen radical attack upon DNA. Intracellular reduction of Cr(VI) to Cr(V) or other species that generate oxygen radicals leads to Cr(V) or oxygen radical attack upon DNA. Arsenite causes chromosome breaks. We propose that arsenic, nickel, and chromium compounds then cause small deletions or mutations in the 5' or 3' regulatory regions of the c-myc and other protooncogenes, resulting in stabilization of c-myc RNA and higher steady-state levels of c-myc RNA and protein. We also postulate that nickel-induced oxygen radical generation, Cr(V) ions or oxygen radicals generated by chromium, and arsenite induce inactivating mutations or deletions in tumor suppressor genes. Arsenic, nickel, or chromium compound-induced neoplastic transformation is postulated to proceed through a combination of activation of c-myc and/or other protooncogenes and inactivation of tumor suppressor. -- Environ Health Perspect 102(Suppl 3) :119-125 (1994) . Key words: morphological and anchorage-independent transformation, carcinogenic metal salts, prostaglandins, oncogenes
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