Tissue kallikrein and the bradykinin B2 receptor are expressed in endometrial and prostate cancers

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Abstract

KLK1/tissue kallikrein is a member of a family of structurally related serine proteases which exhibit a diverse range of enzymic activities. Other members of this family of genes and the bradykinin (B2) receptor have been implicated in cancer processes. The KLK genes are expressed in various organs of the reproductive tract, including the prostate and uterus. In this study, we have examined whether KLK1/tissue kallikrein and the B2 receptor were both expressed in cancers emanating from these organs. We have shown that KLK1/tissue kallikrein and the B2 receptor are expressed, to varying degrees, in prostate disease and 2 human prostate cancer cell-lines, LNCaP and DU145. KLK1 is also expressed in a range of endometrial cancers, although at lower levels than that observed for normal human endometrial tissues. These findings suggest that a functional kallikrein–kinin system is present in prostate disease, in particular, which may be important in the process of tumorigenesis in this tissue.

Introduction

Tissue kallikrein is a member of a family of structurally related serine proteases which exhibit a diverse range of enzymic activities. Three genes have been characterized in the human: KLK1 or tissue kallikrein, KLK2 for which the physiological function is unknown and KLK3 or prostate-specific antigen (PSA) (Clements, 1994). The main sites of expression are the pancreas, salivary gland and kidney (KLK1) and the prostate (KLK2, KLK3) (Chapdelaine et al., 1988; Fukushima et al., 1985). Tissue kallikrein (KLK1) activity, however, has been detected in seminal fluid (Fink et al., 1985; Geiger and Clausnitzer, 1981) but it is not known whether this tissue kallikrein originates from the prostate or another reproductive tract source. PSA is currently the preferred serum marker for monitoring prostate cancer and both the KLK2 and KLK3/PSA genes have been implicated in prostate cancer (Chapdelaine et al., 1988; Oesterling, 1991).

Tissue kallikrein activity has also been detected in the uterus of several species, where it has been implicated in implantation and parturition (Senior and Whalley, 1976; Valdes et al., 1993). We have previously shown, using the sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) method, that all 3 KLK genes are expressed in the human endometrium (Clements and Mukhtar, 1994). PSA has been recently detected in normal breast tissue, amniotic fluid and cancers of the breast, ovary and kidney (reviewed in Diamandis and Yu, 1995). It is not known, however, whether KLK1/tissue kallikrein or other KLK genes are expressed in cancers of the endometrium.

The kallikrein–kinin system has also been implicated in the process of tumorigenesis via the action of bradykinin (Roberts and Gullick, 1989). These data suggest a wider tissue-specific pattern of KLK gene expression in the human than previously thought and an involvement in cancer processes. The aim of this study was to determine whether KLK1/tissue kallikrein and the bradykinin (B2) receptor, the effector receptor for (lys)-bradykinin, the peptide generated by tissue kallikrein, was expressed in both the normal prostate and prostate and endometrial cancers.

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Clinical samples

Normal endometrial tissue was collected from women undergoing dilatation and curettage during routine investigation for essentially male infertility problems. Normal kidney control tissue was obtained at nephrectomy. Tumor tissue was taken at surgery for endometrial cancer or from men undergoing transurethral resection or radical prostatectomy for prostate cancer. Tissues were frozen at −80°C until use. Informed consent was obtained in all circumstances and approval obtained from the Monash

Results

KLK1 expression was assessed by RT-PCR in a range of prostate tissue derived from benign prostatic hyperplasia and adenocarcinoma of the prostate patients. The pattern of expression obtained for KLK1 in these prostate samples is shown on the Southern blot seen in Fig. 1. Although this RT-PCR was not quantitative, there is clearly a range of levels of expression for these different prostate samples. The PCR product was 378 bp, as expected; the second larger band seen on some samples presumably

Discussion

We have demonstrated that KLK1/tissue kallikrein and the bradykinin receptor are expressed in a range of prostate tissue obtained from patients with both benign and malignant prostate disease. The identification of the prostate as a site of expression for KLK1 suggests that the tissue kallikrein activity, detected previously in seminal fluid (Fink et al., 1985; Geiger and Clausnitzer, 1981), may well originate from the prostate. The differential pattern of expression observed for KLK1/tissue

Acknowledgements

We thank Dr. Chris Love, Dr. Arthur Day and Dr. Tom Jobling (Monash Medical Centre, Melbourne) for the prostate and endometrial cancer tissue samples. We also thank Dr. Lois Salamonsen (Prince Henry's Institute of Medical Research) for the normal human endometrial tissue samples and Stephen McPherson (Institute for Reproduction and Development, Melbourne) for cultures of the LNCaP and DU145 cell lines. This work was supported by the NH&MRC of Australia and the Anti-cancer Council of Victoria.

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