₁ Integrin Cytoplasmic Variants Differentially Regulate Expression of the Antiangiogenic Extracellular Matrix Protein Thrombospondin 1

¹Department of Cancer Biology, Prostate Cancer Discovery and Development Program, and ²Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts; ³Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and ⁴Departments of Pathology and Urology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

^* To whom correspondence should be addressed. E-mail: lucia.languino{at}umassmed.edu.

	Abstract

₁ integrins play an important role in regulating cell proliferation and survival. Using small interfering RNA or an inhibitory antibody to ₁, we show here that, in vivo, ₁ integrins are essential for prostate cancer growth. Among the five known ₁ integrin cytoplasmic variants, two have been shown to differentially affect prostate cell functions. The _1A variant promotes normal and cancer cell proliferation, whereas the _1C variant, which is down-regulated in prostate cancer, inhibits tumor growth and appears to have a dominant effect on _1A. To investigate the mechanism by which _1C inhibits the tumorigenic potential of _1A, we analyzed changes in gene expression in cells transfected with either _1C or _1A. The results show that _1C expression increases the levels of an extracellular matrix protein, thrombospondin 1 (TSP1), an angiogenesis inhibitor. TSP1 protein levels are increased upon _1C expression in prostate cancer cells as well as in ₁-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 _1C, prevents proliferation of endothelial cells. In conclusion, our novel findings indicate that expression of the _1C integrin variant in prostate glands prevents cancer progression by up-regulation of TSP1 levels and inhibition of angiogenesis. [Cancer Res 2009;69(13):5374–82]

Key Words: ₁ integrin variants, thrombospondin, prostate cancer, laminin, extracellular matrix