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

Abstract

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 types^2–4. 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 differentiation^5–7. 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 cancers^8,9. 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 vitro^l0. 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 receptors^18,19. 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.