1. ¹Mayo Clinic Cancer Center and Department of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USA
2. ²Arthritis Biology Unit, Novartis Pharmaceuticals, E Hanover, NJ 07936, USA
3. ³Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA

Correspondence: V Shridhar, Division of Experimental Pathology, Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA. E-mail: shridv@exrch.mayo.edu

Received 2 September 2003; Revised 6 October 2003; Accepted 7 October 2003; Published online 5 January 2004.

Abstract

We report here that HtrA1, a candidate tumor suppressor, is downregulated in ovarian cancer. Expression of HtrA1 is downregulated in five of seven ovarian cancer cell lines. In total, 59% of primary ovarian tumors have either a complete absence or markedly reduced levels of HtrA1 expression compared to the brushings of ovarian surface epithelium. Primary ovarian tumors show high frequencies of loss of an allele at microsatellite markers near htrA1 locus on 10q26. Downregulation of HtrA1 in SKOV3 by antisense transfection promotes anchorage-independent growth, while exogenous expression of HtrA1 in OV202 induces cell death. HtrA1-induced cell death is not inhibited by the broad caspase inhibitor, zVAD(OMe)fmk, but instead reflects serine protease activity associated with HtrA1. These observations raise the possibility of HtrA1 as a candidate tumor suppressor involved in promoting serine-protease-mediated cell death and that downregulation of HtrA1 in ovarian cancer may contribute to malignant phenotype.