Document Type : Review Article


1 Department of Genetic science, Faculty of Basic science, University of Azad eslami branch of Damghan, Iran.

2 Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.


Kallikrein related peptidases (KLKs) are a group of serine-like proteases such as chemo trypsin and trypsin, which are regulated by steroid hormones and play a vital role in a variety of natural and physiological functions through their proteolytic activity. However, involvement of these proteases has been reported in many pathological conditions, such as various types of malignancies. Deregulation of the expression of genes encoding kallikrein, including KLK2, is often associated with many types of cancer, in particular prostate cancer. This review provides an overview of the gene and protein structures and function of KLKs particularly, KLK2, at the molecular level, and also summarizes the role of KLK2 in the pathobiology of prostate cancer and the possible mechanisms involved in its progression. Finally, the importance of this protein is studied as a specific diagnostic marker along with PSA marker as well as therapeutic target of KLK2 in treatment of prostate cancer.  A comprehensive understanding the structure and activity of this protein in prostate cancer can provide a valuable tool for future clinical practice that can be used to evaluate the clinical outcome and select the most appropriate treatment strategy. The critical role of KLK2 in promoting cell growth, migration, metastasis, angiogenesis and inhibiting apoptosis in prostate cancer cells, suggests KLK2 as the second diagnostic biomarker along with PSA with high specificity.


1.Boyukozer FB, Tanoglu EG, Ozen M, Ittmann M, Aslan ES. Kallikrein gene family as biomarkers for recurrent prostate cancer. Croatian Medical Journal. 2020;61(5):450.
2.Fuhrman-Luck RA, Loessner D, Clements JA. Kallikrein-related peptidases in prostate cancer: from molecular function to clinical application. EJIFCC. 2014;25(3):269.
3.Avgeris M, Scorilas A. Kallikrein-related peptidases (KLKs) as emerging therapeutic targets: focus on prostate cancer and skin pathologies. Expert opinion on therapeutic targets. 2016;20(7):801-18.
4.Kryza T, Silva ML, Loessner D, Heuzé-Vourc’h N, Clements J. The kallikrein-related peptidase family: Dysregulation and functions during cancer progression. Biochimie. 2016;122:283-99.
5.Stefanini ACB, da Cunha BR, Henrique T, Tajara EH. Involvement of kallikrein-related peptidases in normal and pathologic processes. Disease markers. 2015;2015.
6.Filippou PS, Karagiannis GS, Musrap N, Diamandis EP. Kallikrein-related peptidases (KLKs) and the hallmarks of cancer. Critical reviews in clinical laboratory sciences. 2016;53(4):277-91.
7.Tailor PD, Kodeboyina SK, Bai S, Patel N, Sharma S, Ratnani A, et al. Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types. Oncotarget. 2018;9(25):17876.
8.Kryza T, Bock N, Lovell S, Rockstroh A, Lehman ML, Lesner A, et al. The molecular function of kallikrein‐related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer. Molecular oncology. 2020;14(1):105-28.
9.Wang P, Magdolen V, Seidl C, Dorn J, Drecoll E, Kotzsch M, et al. Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer. British journal of cancer. 2018;119(7):1-9.
10.Avgeris M, Mavridis K, Scorilas A. Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance. Biological chemistry. 2012;393(5):301-17.
11.Prassas I, Eissa A, Poda G, Diamandis EP. Unleashing the therapeutic potential of human kallikrein-related serine proteases. Nature reviews Drug discovery. 2015;14(3):183-202.
12.Xie Z, Li Z, Shao Y, Liao C. Discovery and development of plasma kallikrein inhibitors for multiple diseases. European journal of medicinal chemistry. 2020;190:112137.
13.Kishibe M. Physiological and pathological roles of kallikrein-related peptidases in the epidermis. Journal of dermatological science. 2019;95(2):50-5.
14.Mella C, Figueroa CD, Otth C, Ehrenfeld P. Involvement of kallikrein-related peptidases in nervous system disorders. Frontiers in Cellular Neuroscience. 2020;14.
15.Jaffa MA, Bebu I, Luttrell D, Braffett BH, Lachin JM, Hunt K, et al. Longitudinal Plasma Kallikrein Levels and Their Association With the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC. Diabetes. 2020;69(11):2440-5.
16.Zambon C-F, Prayer-Galetti T, Basso D, Padoan A, Rossi E, Secco S, et al. Effectiveness of the combined evaluation of KLK3 genetics and free-to-total prostate specific antigen ratio for prostate cancer diagnosis. The Journal of urology. 2012;188(4):1124-30.
17.Assel M, Sjöblom L, Murtola TJ, Talala K, Kujala P, Stenman U-H, et al. A Four-kallikrein Panel and β-Microseminoprotein in Predicting High-grade Prostate Cancer on Biopsy: An Independent Replication from the Finnish Section of the European Randomized Study of Screening for Prostate Cancer. European urology focus. 2019;5(4):561-7.
18.Skala W, Utzschneider DT, Magdolen V, Debela M, Guo S, Craik CS, et al. Structure-function analyses of human kallikrein-related peptidase 2 establish the 99-loop as master regulator of activity. Journal of Biological Chemistry. 2014;289(49):34267-83.
19.Felgueiras J, Camilo V, Fardilha M, Jerónimo C. More Than Androgens: Hormonal and Paracrine Signaling in Prostate Development and Homeostasis.  Tissue-Specific Cell Signaling: Springer; 2020. p. 195-223.
20.Sävblom C, Halldén C, Cronin AM, Säll T, Savage C, Vertosick EA, et al. Genetic variation in KLK2 and KLK3 is associated with concentrations of hK2 and PSA in serum and seminal plasma in young men. Clinical chemistry. 2014;60(3):490-9.
21.Adamopoulos PG, Kontos CK, Scorilas A. Discovery of novel transcripts of the human tissue kallikrein (KLK1) and kallikrein-related peptidase 2 (KLK2) in human cancer cells, exploiting Next-Generation Sequencing technology. Genomics. 2019;111(4):642-52.
22.Emami N, Diamandis EP. New insights into the functional mechanisms and clinical applications of the kallikrein-related peptidase family. Molecular oncology. 2007;1(3):269-87.
23.Shang Z, Niu Y, Cai Q, Chen J, Tian J, Yeh S, et al. Human kallikrein 2 (KLK2) promotes prostate cancer cell growth via function as a modulator to promote the ARA70-enhanced androgen receptor transactivation. Tumor Biology. 2014;35(3):1881-90.
24.Lundwall Å, Brattsand M. Kallikrein-related peptidases. Cellular and Molecular Life Sciences. 2008;65(13):2019-38.
25.Diamandis EP, Yousef GM, Luo L-Y, Magklara A, Obiezu CV. The new human kallikrein gene family: implications in carcinogenesis. Trends in Endocrinology & Metabolism. 2000;11(2):54-60.
26.Yousef GM, Diamandis EP. The new human tissue kallikrein gene family: structure, function, and association to disease. Endocrine reviews. 2001;22(2):184-204.
27.Emami N, Diamandis EP. Human tissue kallikreins: a road under construction. Clinica chimica acta. 2007;381(1):78-84.
28.Borgoño CA, Diamandis EP. The emerging roles of human tissue kallikreins in cancer. Nature Reviews Cancer. 2004;4(11):876-90.
29.Mavridis K, Scorilas A. Prognostic value and biological role of the kallikrein-related peptidases in human malignancies. Future Oncology. 2010;6(2):269-85.
30.Thorek DL, Evans MJ, Carlsson SV, Ulmert D, Lilja H. Prostate specific kallikrein-related peptidases and their relation to prostate cancer biology and detection; established relevance and emerging roles. Thrombosis and haemostasis. 2013;110(3):484.
31.Ramsay AJ, Reid JC, Adams MN, Samaratunga H, Dong Y, Clements JA, et al. Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs). Biological chemistry. 2008;389(6):653-68.
32.CHRISTENSSON A, LILJA H. Complex formation between protein C inhibitor and prostate‐specific antigen in vitro and in human semen. European journal of Biochemistry. 1994;220(1):45-53.
33.Leinonen J, Zhang W-M, Stenman U-H. Complex formation between PSA isoenzymes and protease inhibitors. The Journal of urology. 1996;155(3):1099-103.
34.Lilja H. Significance of different molecular forms of serum PSA. The free, noncomplexed form of PSA versus that complexed to alpha 1-antichymotrypsin. The Urologic clinics of North America. 1993;20(4):681.
35.Zhang W-M, Leinonen J, Kalkkinen N, Dowell B, Stenman U-H. Purification and characterization of different molecular forms of prostate-specific antigen in human seminal fluid. Clinical chemistry. 1995;41(11):1567-73.
36.Saedi MS, Zhu Z, Marker K, Liu RS, Carpenter PM, Rittenhouse H, et al. Human kallikrein 2 (hK2), but not prostate‐specific antigen (PSA), rapidly complexes with protease inhibitor 6 (PI‐6) released from prostate carcinoma cells. International journal of cancer. 2001;94(4):558-63.
37.Steuber T, Vickers AJ, Serio AM, Vaisanen V, Haese A, Pettersson K, et al. Comparison of free and total forms of serum human kallikrein 2 and prostate-specific antigen for prediction of locally advanced and recurrent prostate cancer. Clinical chemistry. 2007;53(2):233-40.
38.Mohler J, Bahnson RR, Boston B, Busby JE, D’Amico A, Eastham JA, et al. Prostate cancer. Journal of the National Comprehensive Cancer Network. 2010;8(2):162-200.
39.Shafai S, Moslemi E, Mohammadi M, Esfahani K, Izadi A. Expression of KLK2 gene in prostate cancer. Tehran University Medical Journal TUMS Publications. 2018;75(10):745-51.
40.Nam RK, Zhang WW, Klotz LH, Trachtenberg J, Jewett MA, Sweet J, et al. Variants of the hK2 protein gene (KLK2) are associated with serum hK2 levels and predict the presence of prostate cancer at biopsy. Clinical cancer research. 2006;12(21):6452-8.
41.Stephan C, Jung K, Lein M, Diamandis EP. PSA and other tissue kallikreins for prostate cancer detection. European Journal of Cancer. 2007;43(13):1918-26.
42.Bonk S, Kluth M, Jansen K, Hube‐Magg C, Makrypidi‐Fraune G, Höflmayer D, et al. Reduced KLK2 expression is a strong and independent predictor of poor prognosis in ERG‐negative prostate cancer. The Prostate. 2020;80(13):1097-107.
43.Hannu K, Johanna M, Ulf-Håkan S. KLK-targeted therapies for prostate cancer. Ejifcc. 2014;25(2):207.
44.Deperthes D, Kündig C. Kallikrein-related Peptideases as Pharmaceutical Targets. Kallikrein-related peptidases.1:161-86.
45.Sotiropoulou G, Pampalakis G. Targeting the kallikrein-related peptidases for drug development. Trends in pharmacological sciences. 2012;33(12):623-34.
46.Shaw JL, Diamandis EP. Distribution of 15 human kallikreins in tissues and biological fluids. Clinical chemistry. 2007;53(8):1423-32.
47.Janssen S, Rosen DM, Ricklis RM, Dionne CA, Lilja H, Christensen SB, et al. Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)‐activated thapsigargin prodrug. The Prostate. 2006;66(4):358-68.