Use of Vitamins A and D in Chemoprevention and Therapy of Cancer: Control of Nuclear Receptor Expression and Function

Vitamin A is an essential nutrient which is well known for its role in vision and reproduction 1. Vitamin D is best known for its role in maintaining bone mineral homeostasis. However, over the last 8–10 years, research results have indicated that the active metabolites of these vitamins play a much broader role in regulating the functions of a variety of cell types2–4. The vitamin A metabolites, all-trans retinoic acid and 9-cis retinoic acid regulate growth and differentiation, while retinaldehyde regulates vision. Vitamin D is converted to the active form, 1,25-dihydroxyvitamin D3 (VD3). In addition to regulating Ca++ homeostasis, it regulates hormone production and secretion, myocardial contractility and vascular tone, and growth and differentiation5–7. Early observations that vitamin A deprived animals had a higher incidence of spontaneous and carcinogen-induced tumors suggested a link between this vitamin and cancer. This link was strenthened by epidemiological studies that found a correlation between low vitamin A intake in humans and a higher incidence of certain types of cancers8,9. Laboratory studies have established that all-trans retinoic acid can inhibit the proliferation and stimulate the differentiation of many different types of tumor cells in vitrol0. These results have led to use of all-trans retinoic acid in treating certain cancers such as promyelocytic leukemia, where it induces a high rate of remissions, which are unfortunately of short duration11. This same vitamin A metabolite shows promise for treatment of early pre-malignant lesions of head and neck cancer12 and in combination with γ interferon for controling cervical cancer13. Vitamin D3 receptors have been found in a variety of cells not normally associated with mineral metabolism. The presence of these receptors implies that the cells are responsive to vitamin D. Indeed, vitamin D3 has been found to inhibit human breast cancer cell growth in culture14 and to induce the differentiation of certain leukemic cells7. Use of vitamin D3 for cancer therapy has been limited by problems with hypercalcemia and hypercalciuria. New analogs of vitamin D which retain their ability to inhibit tumor growth or induce differentiation, but have diminished calcium moblilizing activity have recently been developed. Current research is exploring the feasibility of using these new analogs to treat breast and prostate cancer. Vitamin D3 and retinoic acid receptors are located in the nucleus and have a structural organization similar to steroid receptors. While there is only one known receptor for vitamin D3, there are three retinoic acid receptor (RAR) subtypes; RARα, RARβ and RARγ15 Each of these subtypes can generate several isotypes by using different promoters or by differential splicing of the initial transcript16. In addition, there is another class of receptors termed RXR, which have some homology to RAR, but specifically bind the vitamin A metabolite 9-cis-retinoic acid’. There are three subtypes of RXR (RXRα, β, and γ), each of which can form heterodimers with both the RAR, vitamin D3 receptors, as well as other steroid receptors18,19. Since the RARs are expressed in low copy number (~1,000 receptors/cell), it is possibile that the control of response to retinoic acid could be governed by the availability of receptors. To examine this possibility, we tested the ability of several regulatory molecules to alter the expression of these receptors. We found that retinoic acid itself could increase the expression of RARβ and RARγ, while cyclic AMP decreased the expression of all three RAR subtypes.