Comparative effects of all-trans beta-carotene vs. 9-cis beta-carotene on carcinogen-induced neoplastic transformation and connexin 43 expression in murine 10T1/2 cells and on the differentiation of human keratinocytes.

9-cis beta-Carotene was extracted from a commercial extract of the algae Dunaliella salina (Betatene), and its actions on proliferation and gene expression were examined in murine 10T1/2 cells and human HaCaT keratinocytes. The 9-cis isomer was less active than all-trans beta-carotene in reducing proliferation and in upregulating expression of connexin 43 in 10T1/2 cells. However, it had comparable ability to suppress carcinogen-induced neoplastic transformation. When tested in HaCaT cells in organotypic culture, it was less active in inducing connexin 43 expression and suppressing expression of keratin K1. In this assay the all-trans isomer was highly active at 10(-6) M, whereas 10(-5) M 9-cis beta-carotene was required to produce a comparable effect. Only small reductions in expression of the basal keratin 5 were seen. All-trans and 9-cis retinoic acids, potential metabolites of beta-carotene isomers, were studied in the same systems. In contrast to the carotenoids, the 9-cis isomer of retinoic acid was approximately 10-fold more active in suppressing neoplastic transformation and inducing connexin 43 expression in both cell types than the all-trans isomer. The retinoic acid isomers were about equipotent in suppressing K1 expression. Cellular levels of 9-cis beta-carotene were approximately 3.5-fold lower than levels of all-trans beta-carotene, suggesting that part, but not all, of this decreased activity of the 9-cis isomer was due to decreased cell uptake. Thus 9-cis beta-carotene is consistently less active than the all-trans isomer; that 9-cis retinoic acid is, in general, much more potent than the all-trans isomer suggests little or no conversion from the carotenoid to the retinoid under these culture conditions.