Beta1 integrin cytoplasmic variants differentially regulate expression of the antiangiogenic extracellular matrix protein thrombospondin 1.

B1 integrins play an important role in regulating cell proliferation and survival. Using small interfering RNA or an inhibitory antibody to B1, we show here that, in vivo, B1 integrins are essential for prostate cancer growth. Among the five known B1 integrin cytoplasmic variants, two have been shown to differentially affect prostate cell functions. The B1A variant promotes normal and cancer cell proliferation, whereas the B1C variant, which is down-regulated in prostate cancer, inhibits tumor growth and appears to have a dominant effect on B1A. To investigate the mechanism by which B1C inhibits the tumorigenic potential of B1A, we analyzed changes in gene expression in cells transfected with either B1C or B1A. The results show that B1C expression increases the levels of an extracellular matrix protein, thrombospondin 1 (TSP1), an angiogenesis inhibitor. TSP1 protein levels are increased upon B1C expression in prostate cancer cells as well as in B1-null GD25 cells. We show that TSP1 does not affect proliferation, apoptosis, or anchorage-independent growth of prostate cancer cells. In contrast, the newly synthesized TSP1, secreted by prostate cancer cells expressing B1C, prevents proliferation of endothelial cells. In conclusion, our novel findings indicate that expression of the B1C integrin variant in prostate glands prevents cancer progression by up-regulation of TSP1 levels and inhibition of angiogenesis