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Testisin, a Glycosyl-Phosphatidylinositol–Linked Serine Protease, Promotes Malignant Transformation In vitro and In vivo

diaDexus, Inc., South San Francisco, California

Requests for reprints: Jackie Papkoff, diaDexus, Inc., 343 Oyster Point Boulevard, South San Francisco, CA 94080. Phone: 650-246-6502; Fax: 650-246-6598; E-mail: jpapkoff{at}diadexus.com.

Human testisin, a serine protease, is highly expressed in ovarian cancer and premeiotic spermatocytes with relatively little expression in other normal tissues. We first showed that testisin was localized on the surface of cultured tumor cells as a glycosyl-phosphatidylinositol–linked protein. We next explored the biological function of testisin in malignant transformation through manipulation of testisin expression in cell culture model systems. Small interfering RNA–mediated knockdown of endogenous testisin mRNA and protein expression in tumor cell lines led to increased apoptosis and diminished growth in soft agar. Conversely, overexpression of testisin in an epithelial cell line induced colony formation in soft agar as well as s.c. tumor growth in severe combined immunodeficient mice. A catalytic domain mutant was unable to induce soft-agar growth indicating that testisin protease activity is required for transformation. Ectopic expression of testisin in a human ovarian cancer cell line without endogenous testisin expression, led to the formation of larger tumors in severe combined immunodeficient mice. Data presented here provide the first demonstration that testisin can promote cellular processes that drive malignant transformation. Our functional data coupled with the restricted normal tissue distribution of testisin and its overexpression in a majority of ovarian cancers validates this cell surface protein as a target for therapeutic intervention.

Key Words: Testisin • ovarian cancer • GPI-linked • serine protease • membrane protease

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