Kallikreins 5, 6 and 10 Differentially Alter Pathophysiology and Overall Survival in an Ovarian Cancer Xenograft Model

Abstract

Human tissue kallikreins (KLKs) are members of a multigene family of serine proteases aberrantly expressed in many cancer types. In ovarian cancer, 12 KLKs are upregulated, and of those KLK5, 6 and 10 have been the focus of investigations into new diagnostic and prognostic biomarkers. However, little is known about the contributions of KLK5, 6 and 10 to ovarian cancer pathophysiology.In this study, a panel of 13 human ovarian cancer cell lines was screened by ELISA for secretion of KLK5, 6, 8, 10, 13, and 14. The ES-2 cell line, devoid of these kallikreins, was transfected with expression vectors of KLK5, 6 and 10 individually or in pairs. Co-expression of KLK5, 6 and 10 was correlated with lessened aggressivity of ovarian cancer cell lines as defined by reduced colony formation in soft agar and tumorigenicity in nude mice. ES-2 clones overexpressing KLK5, 10/5, 10/6, 5/6 made significantly fewer colonies in soft agar. When compared to control mice, survival of mice injected with ES-2 clones overexpressing KLK10, 10/5, 10/6, 5/6 was significantly longer, while KLK6 was shorter. All groups displaying a survival advantage also differed quantitatively and qualitatively in their presentation of ascites, with both a reduced incidence of ascites and an absence of cellular aggregates within those ascites. The survival advantage conferred by KLK10 overexpression could be recapitulated with the exogenous administration of a recombinant KLK10. In conclusion, these findings indicate that KLK5, 6 and 10 may modulate the progression of ovarian cancer, and interact together to alter tumour pathophysiology. Furthermore, results support the putative role of KLK10 as a tumour suppressor and suggest it may hold therapeutic potential in ovarian cancer.

Paclitaxel Resistance and Multicellular Spheroid Formation Are Induced by Kallikrein-Related Peptidase 4 in Serous Ovarian Cancer Cells in an Ascites Mimicking Microenvironment

“…Thus, conceivably the KLK4 functional blocking antibody is also inhibiting non proteolytic KLK4 effects although the data from the use of the KLK4 selective active site SFTI inhibitor clearly indicates that there is a significant proteolytic component to this effect as well. Consistent with this argument, a recent study showed that catalytically inactive KLK10, another member of this gene family, displayed a role as a tumor suppressor on ES2 ovarian cancer cells both in vitro and in vivo [58]. An earlier study revealed that two prostate specific antigen (PSA, also known as KLK3) blocking antibodies, one inhibiting enzymatic activity and one not affecting catalytic activity, both inhibited the biological function of this kallikrein, suggesting that PSA also has an alternative function via protein-protein interaction [59].…”

Evolution of the Plasma and Tissue Kallikreins, and Their Alternative Splicing Isoforms

“…Alternatively, expression of KLK protein isoforms with no protease activity may indicate that KLKs have other functions, at least in human. Indeed, KLK10 has been reported to lack trypsin-like enzymatic activity in ovarian ascites fluid [54], although overexpression of KLK10 is associated with lessened aggressivity of ovarian cancer [55]. Also, it has been reported that the proteolytic activity of PSA is not necessary for its role in generating reactive oxygen species (ROS) in prostate cancer [56]; however, more recent reports indicate that the enzymatic activity of PSA is linked to inhibition of ROS scavenging [57] and to the growth of prostate tumors [58].…”

The KLK5 protease suppresses breast cancer by repressing the mevalonate pathway

“…Furthermore, we show that inhibition of EMTs may underlie the cancer suppressing effects of KLK5. Recently, it was reported that reactivation of KLK5 reverted the malignancy of ES-2 ovarian cancer cells [26]; however, no mechanistic insight has been provided. A novel and very intriguing finding of our study is that expression of KLK5 is associated with alteration in several genes encoding enzymes and regulatory proteins of the mevalonate pathway, including the induction of SREBF1 transcription factor.…”