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 D unaliella salina (Betatene), and ifs actions on proliferation and gene expr ession 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 neoplas tic transformation. When tested in HaCaT cells in organotypic culture, it w as less active in inducing connexin 43 expression and suppressing expressio n of keratin KI. 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 com parable effect. Only small reductions in expression of the basal keratin 5 were seen. All-trans and 9-cis retinoic acids, potential metabolites of bet a -carotene isomers, were studied in the same systems. In contrast to the c arotenoids, the 9-cis isomer of retinoic acid was similar to 10-fold more a ctive in suppressing neoplastic transformation and inducing connexin 43 exp ression in both cell types than the all-trans isomer. The retinoic acid iso mers were about equipotent in suppressing KI expression. Cellular levels of 9-cis beta -carotene were similar to3.5-fold lower than levels of all-tran s beta -carotene, suggesting that part, but not all, of this decreased acti vity 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 s uggests little or no conversion from the carotenoid to the retinoid under t hese culture conditions.