UP-REGULATION OF GAP JUNCTIONAL COMMUNICATION AND CONNEXIN43 GENE-EXPRESSION BY CAROTENOIDS IN HUMAN DERMAL FIBROBLASTS BUT NOT IN HUMAN KERATINOCYTES

Consumption of dietary carotenoids has been statistically associated with decreased risk of cancer at several anatomic sites. In a model murine system of carcinogenesis (the 10T1/2 assay), we have previously shown that carotenoids can inhibit chemically and physically induced neoplastic transformation. This action is strongly correlated with the ability of carotenoids to increase gap-junctional communication (GJC) by induction of connexin43 (Cx43) gene expression. Here we extend these studies to human foreskin-derived dermal fibroblasts and keratinocytes. in fibroblasts, beta-carotene and canthaxanthin at concentrations between 10(-5) and 3 x 10(-6) M were found to strongly enhance GJC in a dose- and time-dependent manner. This was accompanied by an increase in the number of immunofluorescent junctional plaques recognized by an anti-Cx43 antibody and by an increase in Cx43 protein level as determined by western blot analysis. No decrease in proliferation rates was detected by [H-3]thymidine labeling. Human keratinocytes grown in monolayer culture did not respond to carotenoids in terms of GJC as measured by dye transfer, immunofluorescent analysis of Cx43 distribution, or Cx43 levels as measured by western blotting. Both cell types accumulated high levels of carotenoids. Because canthaxanthin, which has no known provitamin A activity in mammals, is as active in fibroblasts as is beta-carotene, the carotenoid with the highest provitamin A activity, the induction of GJC and Cx43 expression by carotenoids in human dermal fibroblasts seems unrelated to their provitamin A status. The lack of response of keratinocytes suggests differences in regulation of Cx43 expression or in carotenoid processing. (C) 1995 Wiley-Liss Inc.