1 alpha,25-dihydroxyvitamin D-3 and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells

Vitamin D and its derivatives (deltanoids) are potent regulators of cell pr oliferation and differentiation. Targeted production of proteolytic enzymes like serine proteases and metalloproteinases is an important part of the i nvasive process of cancer cells. Treatment with 1 alpha 25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3] decreases the invasive properties of breast car cinoma cells. Here we have analyzed the effects of 1 alpha,25(OH)(2)D-3 and its synthetic analogues on the secretion and cell surface association of t he components of the plasminogen activator (PA) system and on the secretion of certain matrix metalloproteinases (MMPs) and their inhibitors in MDA-MB -231 breast carcinoma cells. Deltanoids were able to decrease the secretion of urokinase PA and tissue-type PA activity in a dose-dependent manner and to increase PA inhibitor 1 secretion, leading to reduced total PA activity . CB1093 was the most potent analogue, effective at concentrations several logarithms lower than 1 alpha,25(OH)(2)D-3. Transient transfection of diffe rent urokinase PA promoter reporter constructs to HT-1080 fibrosarcoma indi cator cells indicated that vitamin D-responsive sequences were located betw een nucleotides -2350 and -1870 in the 5' region of the promoter. Treatment of MDA-MB-231 cells with 1 alpha,25(OH)(2)D-3 or other deltanoids also res ulted in decreased MMP-9 levels in association with increased tissue inhibi tor of MMP 1 activity. Membrane-type 1-MMP expression or proteolytic proces sing were not appreciably affected by deltanoids, Vitamin D and its analogu es caused a decrease in Matrigel invasion assays of MDA-MB-231 cells. Cance r cell invasion is associated with coordinated secretion of proteolytic enz ymes and their inhibitors. Vitamin D and its derivatives can evidently infl uence invasive processes by two means: (a) decreasing the expression and ac tivity of cell invasion-associated serine proteases and metalloproteinases; and (b) inducing their inhibitors.