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Cathepsins B and D Activity and Activity Ratios in Normal Ovaries, Benign Ovarian Neoplasms, and Epithelial Ovarian Cancer

Depart of Obstetrics, Gynecology and Women's Health. The University of Minnesota Medical Schoola; University of Minnesota Cancer Center, Minneapolis, Minnesota downs{at}umn.edu

Paul H. Lima, MS

Robin L. Bliss, MS

Charles H. Blomquist, PhD

Depart of Obstetrics, Gynecology and Women's Health. The University of Minnesota Medical Schoola; University of Minnesota Cancer Center, Minneapolis, Minnesota

Objective: Cathepsins B (CB) and D (CD) belong to a family of protease felt to be important in tumor metastasis and invasion. It has been suggested that both enzymes play a role the progression of epithelial ovarian cancer and they have been investigated as potential biomarkers for ovarian cancer. Our objective was to determine if activity ratios of these two isoforms might enhance their usefulness as biomarkers.

Methods: Ovarian cancer cell lines and snap-frozen archived tissue samples were sonicated and cathepsin activities were assayed fluorometrically with cathepsin-specific peptide substrates in combination with specific inhitors. Tissue specimens were divided into four groups: normal ovary, benign neoplasm, early-stage (I/II) cancer, and late-stage (III/IV) cancer. Median CB and CD activity and the ratio of CB to CD (CB/CD) were compared using the Wilcoxon rank sum test. Nonparametric Spearman correlation was used to determine associations between CA-125 and cathepsin activity. Logistic regression was used to test the association between cathepsin activity and malignancy.

Results: In cell lines and tissue, CD activity remained relatively constant, while CB activity varied. CB activity was greatest in cancer tissue. Elevated serum CA-125 was associated with elevations in CB activity and CB/CD but not CD activity. Elevated CB activity and CB/CD as well as increasing CA-125 and age are all associated with malignancy. Multiple logistic regression shows that CB activity and age best predict malignancy status.

Conclusions: CB activity is associated with invasive ovarian neoplasm. Our results do not suggest that the ratio of activity between CB and CD provides any additional information than CB activity alone. Both tissue CB activity and CB/CD activity ratios correlate with serum levels of CA-125; however there is no correlation between CD activity and CA-125.

Key Words: Ovarian cancer • cathepsin B • cathepsin D • proteases

Journal of the Society for Gynecologic Investigation, Vol. 12, No. 7, 539-544 (2005)
DOI: 10.1016/j.jsgi.2005.06.009


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