Kallikrein-Related Peptides in Cancer Biology

Kallikrein-related peptides constitute a family of 15 secreted serine proteases (KLK1–15) that regulate numerous physiological processes through proteolytic activation of growth factors, cytokines and cell-surface receptors. Aberrant KLK expression and activity have been documented across a wide range of malignancies, where they contribute to tumour cell proliferation, migration, extracellular matrix remodelling and immune evasion. The KLK activome—a complex network of inter-KLK activation cascades—governs the precise spatial and temporal activity of individual peptidases. In cancer, dysregulation of this activome can amplify oncogenic signals mediated by protease-activated receptors, transforming growth factor-β family ligands and adhesion molecules. KLKs also hold promise as diagnostic or prognostic biomarkers, given their detectable secretion into bodily fluids and association with clinical outcomes. Moreover, selective inhibition or modulation of KLK activity is emerging as a potential therapeutic strategy to curb tumour growth, invasion and metastasis.

Research from Nature Portfolio

Recent studies have elucidated a novel mechanism by which kallikrein-8 (KLK8) mediates the processing of the Activin-A precursor independently of the canonical convertase furin. In melanoma cells, transient acidification exposes a cryptic KLK8 cleavage site within pro-Activin-A, generating a half-processed intermediate that enhances tumour growth. Functional screening identified KLK8 as the responsible protease, and silencing of KLK8 in syngeneic graft models markedly suppressed Activin-A-driven tumour expansion. These findings reveal an auxiliary proteolytic pathway that complements furin activity and nominate KLK8 as a potential target to attenuate Activin-A-dependent tumour progression.

Kallikrein-Related Peptides in Cancer Biology publication trend

The graph below shows the total number of articles in kallikrein-related peptides in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Kallikrein-related peptidase: One of fifteen secreted serine proteases (KLK1–KLK15) involved in proteolytic cascades that regulate growth factors and receptors.

Serine protease: An enzyme that utilises a serine residue in its active site to cleave peptide bonds in substrate proteins.

Furin-independent hemicleavage: Partial proteolytic processing of a precursor protein by a non-furin enzyme, yielding a half-processed intermediate.

Activin-A precursor: The dimeric pro-form of a TGF-β family cytokine that requires extracellular cleavage for bioactivation and receptor binding.

Protease-activated receptor (PAR): A G protein-coupled receptor activated by irreversible proteolytic cleavage of its extracellular N-terminus.

References

1. Functional Roles of Human Kallikrein-related Peptidases*. Journal of Biological Chemistry (2009).
2. Involvement of Kallikrein‐Related Peptidases in Normal and Pathologic Processes. Disease Markers (2015).
3. Activation Profiles and Regulatory Cascades of the Human Kallikrein-related Peptidases*. Journal of Biological Chemistry (2007).
4. Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types. Oncotarget (2018).
5. Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers. Molecular Oncology (2023).
6. Kallikrein-8 mediates furin-independent Activin-A precursor processing to stimulate tumor growth in melanoma. Nature Communications (2025).
7. Kallikrein-Related Peptidase 12 (KLK12) in Breast Cancer as a Favorable Prognostic Marker. International Journal of Molecular Sciences (2023).
8. Structure-based identification of bioactive phytochemicals targeting kallikrein-related peptidase 2 for prostate cancer therapy. Frontiers in Chemistry (2025).