Upregulation of connexin 43 by retinoids but not by non-provitamin A carotenoids requires RARs.
Expression of connexin 43 (Cx43) is correlated with reduced indexes of neoplasia and is upregulated by cancer-preventive retinoids and carotenoids in nontransformed human and murine fibroblasts and keratinocytes. The molecular mechanism of upregulation, however, is poorly understood. Three retinoic acid receptor (RAR) antagonists (Ro 41-5253, BMS453, and BMS493) were capable of suppressing retinoid-induced Cx43 protein expression in 10T1/2 cells. However, Ro 41-5253 did not suppress protein expression by the non-provitamin A carotenoids astaxanthin or lycopene. In contrast, Cx43 induction by astaxanthin but not by a RAR-specific retinoid was inhibited by GW9662, an antagonist of peroxisome proliferator activated receptor-gamma activation. Simultaneous treatment with the maximally effective concentration of a retinoid and with beta-carotene or the non-provitamin A carotenoid astaxanthin resulted in supraadditive upregulation of Cx43 expression, again indicating separate mechanisms of gene regulation by these two cancer preventive agents.
Vine
Alex L
AL
Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu 96813, USA.
Bertram
John S
JS
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D002338:Carotenoids / Q000494:pharmacology*; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000517:prevention & control; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D024341:Xanthophylls; D019207:beta Carotene / Q000031:analogs & derivatives / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D001565:Benzoates; D018031:Connexin 43; D047495:PPAR gamma; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D024341:Xanthophylls; D019207:beta Carotene; D002338:Carotenoids; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; C005948:astaxanthine