Signaling pathways for vitamin D-induced differentiation: implications for therapy of proliferative and neoplastic diseases.

The physiological form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 (1,25D3) is not only a powerful regulator of calcium homeostasis but also a hormone with important roles in cell growth and differentiation. The differentiating effects of 1,25D3 have been studied extensively in a large number of in vitro systems but primarily using cultured leukemia cells, keratinocytes, and bone cells. In spite of this attention, the understanding of the mechanisms that lead to the diverse forms of cell differentiation by 1,25D3 is fragmentary. It seems likely, however, that the effects of 1,25D3 on calcium homeostasis and on cell differentiation are both signaled by direct effects on the cell membrane and by the transduction of the signal to the genome. The direct effect may be mediated by a hypothetical membrane recognition element, the G proteins, phosphoinositide metabolism, and protein kinase C (PKC). Signals to the nucleus may include PKC, the Ca2+ gradient, and protein phosphorylation cascades, but the protein receptor (VDR) plays a principal role in this form of signal transduction. The VDR interacts with the promoter elements of a number of nuclear genes, either as a homodimer or a heterodimer with a retinoid or orphan receptors. The key nuclear responses include the increased expression of phenotype-specifying proteins and the appearance of G1/S and G2+M cell cycle blocks, which result in cessation of cell proliferation. The attempts to improve control of neoplastic cell proliferation will depend on a selective exploitation of these properties of 1,25D3 to design novel analogs of 1,25D3 with low hypercalcemic but high differentiation-inducing properties. It is anticipated that a better understanding of the multiple pathways that transduce the signals from 1,25D3 to the nucleus and to the cell membrane, a consideration of the structure-function relationships of the derivatives of 1,25D3, and the use of synergistic combinations of 1,25D3 with other biological response modifiers or cytotoxic drugs will lead to improved therapy of several hyperproliferative and malignant diseases.