Potentiation of CalciumāMediated Stimulation of DNA Synthesis by Ethanol in Human and Mouse Fibroblasts (original) (raw)
1999, Alcoholism Clinical and Experimental Research
Alcohol abuse is a risk factor for cancers of the gastrointestinal tract, and it also can precipitate psoriasis characterized by hyperproliferation of epidermal cells. Because these effects of alcohol may involve stimulation of ccll growth, and ethanol (EtOH) was shown to enhancc DNA synthesis in mouse fibroblasts and cpidermal cclls. wc conducted a study to determine whcthcr EtOH can also stimulate mitogcnesis in human fibroblasts and keratinocytes. In kcratinocytes, EtOH had no cffccts on mitogenesis aftcr shorter (17-hr) treatments. but it partially preventcd inhibition of DNA synthesis elicited by longer treatments (3-4 days) with 2 mM calcium (Ca'+), a differentiation-inducing agent. In contrast, trcatmcnt of serum-starved zinc-treatcd (40 wM) human skin fibroblasts with 50-60 mM EtOH for 17 hr resulted in increased DNA synthcsis. EtOH-induced DNA synthesis was blocked by 1 mM EGTA, a specific Ca" chelator. Despite the presence of 1.8 mM Ca" in the ccll culture medium, thc addition of 1 mM extra Ca" (final concentration, 2.8 mM) for 17 hr induced DNA synthesis, prcsumably mediated by Ca'+ rcccptors. In cight independent human skin fibroblast lines examincd, treatment with EtOH for 46 hr, but not for 17 hr, invariably enhanced the effects of Ca'+ on DNA synthesis, consistent with synergistic stimulation of cell prolifcration by EtOH and Ca". Ncomycin, a Ca" rcccptor agonist, and EtOH also exerted synergistic effects on DNAsynthesis aftor longer (46-hr) treatments. In mouse NIH 3T3 fibroblasts, both EtOH-and Ca' ' -enhanced DNA synthesis aftcr 17-hr treatment, but they stimulated cell proliferation only in combination. The results indicate that in human fibroblasts, EtOH can potentiate the longer-term effects of high concentrations of Ca' ' on DNA synthesis whereas, in kcratinocytes, EtOH may inhibit Ca''.-induced differentiation.