KLK3

Official Full Name

kallikrein related peptidase 3

Organism

Homo sapiens

GeneID

354

Background

Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. The gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. It encodes a single-chain glycoprotein, a protease which is synthesized in the epithelial cells of the prostate gland, and is present in seminal plasma. It is thought to function normally in the liquefaction of seminal coagulum, presumably by hydrolysis of the high molecular mass seminal vesicle protein. The serum level of this protein, called PSA in the clinical setting, is useful in the diagnosis and monitoring of prostatic carcinoma. Alternate splicing of this gene generates several transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]

Synonyms

APS; PSA; hK3; KLK2A1;

Bio Chemical Class

Peptidase

Protein Sequence

MWVPVVFLTLSVTWIGAAPLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHPQWVLTAAHCIRNKSVILLGRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSHDLMLLRLSEPAELTDAVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVISNDVCAQVHPQKVTKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALPERPSLYTKVVHYRKWIKDTIVANP

Open

Disease

Arteries/arterioles disorder, Prostate cancer, Prostate hyperplasia

Approved Drug

Clinical Trial Drug

6 +

Discontinued Drug

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Detailed Information

Prostate-specific antigen (PSA), also known as γ-seminoprotein or kallikrein-related peptidase 3 (KLK3), is a single-chain glycoprotein and serine protease secreted by prostatic epithelial cells. In the bloodstream, PSA exists in both free (fPSA) and complexed (cPSA) forms and plays a role in semen liquefaction and sperm motility activation. Beyond its physiological functions, PSA is implicated in various signaling pathways associated with prostate cancer, including those governing proliferation, invasion, metastasis, angiogenesis, apoptosis, immune response, and tumor microenvironment regulation. These multifaceted roles make PSA a significant molecular target for prostate cancer treatment.

Role of PSA in Prostate Cancer

PSA is a well-established blood biomarker for prostate cancer recurrence, with serum levels correlating with disease progression. However, its diagnostic specificity is limited, leading to the development of enhanced assays such as PSA velocity, PSA density, the Prostate Health Index (PHI), and the 4Kscore, which aim to improve diagnostic accuracy by incorporating additional PSA-related metrics.

KLK3 involvement in regulating angiogenesis and lymphangiogenesis via VEGF-C and VEGF-D activation under hypoxia and tumor microenvironment conditions. Figure 1. Proposed placement of KLK3 into the regulatory network of angiogenesis and lymphangiogenesis. (Lin HY, et al., 2021)

Functionally, PSA contributes to maintaining cancer cell growth and modulating apoptosis. Within the tumor microenvironment, PSA influences prostate cancer progression by affecting cell proliferation, angiogenesis, and metastatic potential. Notably, PSA can stimulate the expression of tumor suppressor genes and participate in immune responses against tumor cells by activating cytotoxic T lymphocytes (CTLs). Furthermore, PSA serves as a valuable imaging biomarker, aiding in the detection of malignant regions within the prostate and identifying metastatic sites.

Clinical Value of PSA

Tumor Marker for Prostate Cancer: Under normal physiological conditions, PSA levels in serum are low, typically within the reference range of 0–4 ng/mL. However, malignant transformation of prostate tissue disrupts cellular architecture, leading to increased PSA leakage into the bloodstream and elevated serum concentrations. This characteristic elevation makes PSA a crucial tumor marker for prostate cancer detection and monitoring.

Targeted Therapies: Advancements in targeted therapies have focused on PSA and its associated signaling pathways. Approaches include the development of small-molecule inhibitors that target PSA-activated cell surface receptors or downstream signaling components. Additionally, bispecific antibodies have been engineered to simultaneously bind PSA and immune effector cells, such as T cells, thereby enhancing the immune-mediated cytotoxicity against tumor cells. Antibody-drug conjugates (ADCs) targeting PSA are also under investigation, wherein antibodies specific to PSA are conjugated with cytotoxic agents to deliver targeted chemotherapy to prostate cancer cells.

These therapeutic strategies are part of a broader effort to exploit PSA's dual role as both a biomarker and a functional participant in prostate cancer pathophysiology, aiming to improve diagnostic precision and treatment efficacy.

References

Lin HY, Huang PY, Cheng CH, et al. KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness. Sci Rep. 2021;11(1):9264.
Koistinen H, Künnapuu J, Jeltsch M. KLK3 in the Regulation of Angiogenesis-Tumorigenic or Not? Int J Mol Sci. 2021;22(24):13545.

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