chapter  12
22 Pages

Modulation of Gene Expression by Dietary Carotenoids and Retinoids: Role in Cancer Prevention

State of Cells: Chemical Oxidative Damage ....................................... 316 12.3 Carotenoids Modulate Expression of Drug Metabolizing Enzymes ... 319

12.3.1 Effects in the Liver ................................................................. 319 12.3.2 Modulation of Signaling Pathways in the Lung..................... 320

12.4 Retinoids and Dietary Carotenoids as Cancer Preventive Agents ....... 321 12.5 Retinoids and Carotenoids Inhibit Carcinogen-Induced Neoplastic

Transformation in Culture ................................................................... 322 12.6 Gap Junctional Communication and Carcinogenesis .......................... 324 12.7 Carotenoids Induce Cx43 Irrespective of Their Provitamin A

or Antioxidant Properties ..................................................................... 326 12.8 Forced Expression of Cx43 in Human Carcinoma Cells Reduces

Markers of Malignancy ........................................................................ 327 12.9 Mechanistic Studies of Cx43 Induction by Carotenoids ..................... 330 12.10 Lycopene Modulates the IGF-I Signaling Pathway ............................. 331 12.11 Conclusion ........................................................................................... 331 References ......................................................................................................... 332

From a biological perspective, carotenoids can be most easily classifi ed as those that possess provitamin A activity and those that do not. From a chemical perspective, carotenoids are generally classifi ed as the hydrocarbon carotenoids, of which the prototype would be beta-carotene, a C40H56 hydrocarbon containing 2 betaionone rings and 11 conjugated double bonds; and the xanthophylls, oxygenated carotenoids such as lutein (C40H56O2), found in all green leaves, with hydroxyl groups on each of the rings. Both compounds can be found at micromole amounts in human serum and are obtained from consumption of carotenoid-containing fruits and vegetables [1]. Carotenoids also include straight-chain molecules, such as lycopene (C40H56), the red pigment found in tomatoes. The principal structural features of carotenoids are the possession of a methyl-substituted, conjugated double-bond system, refl ecting their synthesis from isoprene units in the plant [2]. Until recently, carotenoids were considered to have two major biological functions: fi rst, the possession of a beta-ionone ring by the provitamin A carotenoids allows their bioconversion in mammals to retinoids-compounds with essential roles in vision and in normal growth and differentiation [3]; and second, the conjugated double-bond system possessed by all carotenoids allows them to be effective lipidphase antioxidants that can protect cell organelles from free-radical mediated damage. As to be discussed later, there is now evidence that carotenoids can directly regulate the expression of genes protective against carcinogenesis. Retinoids are those compounds capable of activating the retinoic acid nuclear receptors (RAR and RXRs); the natural ligands for these receptors are all-trans retinoic acid and 9-cis retinoic acid, respectively. Structures of representative carotenoids and retinoids are shown in Figure 12.1. The role of carotenoids in the biosynthesis of retinaldehyde, the visual pigment in the retina, is a separate and discrete function that will not be further considered here. Instead, we will concentrate on the role of carotenoids and retinoids as modulators of expression of genes directly or indirectly involved in carcinogenesis.