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Despite campaigns and improvements in detection and treatment, lung cancer continues to increase worldwide and represents a major public health problem. One approach to treating patients suffering from lung cancer is to target surface receptors overexpressed on tumor cells, such as GPCR-family kinin receptors, and proteases that control tumor progression, such as kallikrein-related peptidases (KLKs). These proteases have been visualized in recent years due to their contribution to the progression of cancers, such as prostate and ovarian cancer, facilitating the invasive and metastatic capacity of tumor cells in these tissues. In fact, KLK3 is the specific prostate antigen, the only tissue-specific biomarker used to diagnose this malignancy. In lung cancer to date, evidence indicates that KLK5, KLK6, KLK8, KLK11, and KLK14 are the major peptidases regulated and involved in its progression. The expression levels of KLKs in this neoplasm are modulated by the secretome of the different cell types present in the tumor microenvironment, the cancer subtype and the tumor stage, among others. Considering the multiple functions of kinin receptors and KLKs, this review highlights their roles, even considering the SARS-CoV-2 effects. Since lung cancer is often diagnosed in advanced stages, our efforts should focus on early diagnosis, validating for example specific KLKs, especially in high-risk populations such as smokers and people exposed to carcinogenic fumes, oil fields, and contaminated workplaces, unexplored fields to investigate. Furthermore, their modulation could be considered as a promising approach in lung cancer therapeutics. [ABSTRACT FROM AUTHOR]

The serine protease inhibitor Kazal type (SPINK) family includes SPINK1-14 and is the largest branch in the serine protease inhibitor family. SPINKs play an important role in pancreatic physiology and disease, sperm maturation and capacitation, Nager syndrome, inflammation and the skin barrier. Evidence shows that the unregulated expression of SPINK1, 2, 4, 5, 6, 7, and 13 is closely related to human tumors. Different SPINKs exhibit various regulatory modes in different tumors and can be used as tumor prognostic markers. This article reviews the role of SPINK1, 2, 4, 5, 6, 7, and 13 in different human cancer processes and helps to identify new cancer treatment targets. [ABSTRACT FROM AUTHOR]

Objective: Oxidative stress is considered a prime contributor to skin aging. Aged skin can be characterized by increased wrinkles and dry and dull appearance, which are associated with increased collagen degradation and inadequate desquamation, respectively. We investigated the antioxidant and skin anti-aging effects of a Ginkgo biloba leaf extract (GLE), an aqueous ethanol extract of Ginkgo biloba leaves, and the molecular mechanisms involved, using HaCaT keratinocytes. Methods: HaCaT cells were pretreated with GLE (0–15 μg/mL) and then treated with H2O2 (0.2 mM), and the cell viability and metalloproteinase 1 (MMP-1) protein level were measured. To investigate the mechanisms underlying the GLE's effects, the cells were incubated with GLE, and then glutathione content, cell migration rate, and the levels of proteins, i.e., MMPs, Kallikrein-related peptidases (KLKs), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and mitogen-activated protein kinases, were measured. Results: GLE pretreatment caused decreases in cytotoxicity and the level of MMP-1, a key enzyme that degrades collagen in dermis, induced by H2O2 in HaCaT cells. GLE (5–15 μg/mL) caused increases in glutathione content and HO-1 level in cells, which appeared to be associated with the increase in Nrf2, a principal transcription factor for the antioxidant response. GLE also increased keratinocyte migration, which might result from the increase in KLK-7, a key enzyme that degrades corneodesmosomes and thus stimulates desquamation of corneocytes in epidermis. GLE increased the phosphorylation of c-Jun N-terminal protein kinase and extracellular signal-regulated kinase, which might contribute to the antioxidant and skin anti-aging effects of GLE demonstrated in our results. Conclusions: Our results suggest that GLE may have skin anti-aging effects by protecting keratinocytes against excessive oxidative stress via stimulation of antioxidant response, reducing wrinkle formation via a decrease in MMP-1 expression, and stimulating desquamation via an increase in KLK-7 expression. [ABSTRACT FROM AUTHOR]

Keywords: activity-based probes; ABPs; kallikrein-related peptidases; KLKs; KLK-ABPs; KLK proteolytic cascades; activography; theranostic ABPs EN activity-based probes ABPs kallikrein-related peptidases KLKs KLK-ABPs KLK proteolytic cascades activography theranostic ABPs 401 403 3 11/29/22 20220101 NES 220101 Dear Editors We read with great interest the recent publication by Lee et al.,[1] in which the important paper by Lovell et al.[2] is presented as the first report of activity-based protein profiling (ABPP) selective for individual KLKs in a complex biological context. KLK-ABPs, KLK proteolytic cascades, theranostic ABPs, activity-based probes, ABPs, kallikrein-related peptidases, KLKs, activography. [Extracted from the article]

The kallikrein family comprises tissue kallikrein and 14 kallikrein-related peptidases (KLKs) recognized as a subgroup of secreted trypsin- or chymotrypsin-like serine proteases. KLKs are expressed in many cellular types where they regulate important physiological activities such as semen liquefaction, immune response, neural development, blood pressure, skin desquamation and tooth enamel formation. Tissue kallikrein, the oldest member and kinin-releasing enzyme, and KLK3/PSA, a tumor biomarker for prostate cancer are the most prominent components of the family. Additionally, other KLKs have shown an abnormal expression in neoplasia, particularly in breast cancer. Thus, increased levels of some KLKs may increase extracellular matrix degradation, invasion and metastasis; other KLKs modulate cell growth, survival and angiogenesis. On the contrary, KLKs can also inhibit angiogenesis and produce tumor suppression. However, there is a lack of knowledge on how KLKs are regulated in tumor microenvironment by molecules present at the site, namely cytokines, inflammatory mediators and growth factors. Little is known about the signaling pathways that control expression/secretion of KLKs in breast cancer, and further how activation of PAR receptors may contribute to functional activity in neoplasia. A better understanding of these molecular events will allow us to consider KLKs as relevant therapeutic targets for breast cancer. [ABSTRACT FROM AUTHOR]

Novel molecular markers that address the heterogeneity of breast cancer (BC) and provide meaningful prognostic information for BC patients are needed. Kallikrein-related peptidase 6 (KLK6) is aberrantly expressed and functionally implicated in BC and, like other members of the KLK family, may prove a useful molecular tool for clinical management. Our objective was to assess, for the first time, the clinical relevance of KLK6 mRNA expression in BC. Total RNA was isolated from 165 breast tumors, as well as 100 adjacent non-cancerous tumor specimens. After cDNA synthesis, and following quality control, quantitative real-time PCR for KLK6 expression analysis took place. Receiver operating characteristic curves were constructed in order to assess the ability of KLK6 mRNA expression levels to differentiate between molecular BC subtypes. Survival analyses, using DFS as endpoint, were performed at the univariate and multivariate levels. Publicly available BC databases and online survival analysis tools were used to validate our findings. A significant downregulation of KLK6 mRNA expression was observed in BC tissue sections compared to the non-cancerous component (P < 0.001). The expression of KLK6 is positively associated with tumor grade (P = 0.038) and is overexpressed in TNBC and HER2-positive tumors (P < 0.001). Aberrant KLK6 expression predicts the clinical outcome of BC patients in terms of DFS, independently of currently used prognostic markers (HR = 7.11, 95% CI = 1.19-42.45). The differential expression of KLK6 and its association with unfavorable outcome in BC patients was validated via in silico analyses. Although an independent external cohort is necessary to confirm our findings, we proved for the first time that KLK6 can provide independent prognostic information for BC patients. [ABSTRACT FROM AUTHOR]

Purpose: Despite recent research advantages on the molecular and subcellular background, bladder cancer (BlCa) remains a clinically neglected malignancy. This is strongly reflected by the generic approach of disease diagnosis and management. Additionally, patients' prognosis became a rather demanding task due to the great disease heterogeneity. Here, we aimed to evaluate, for the first time, the clinical value of KLK13 in BlCa. Methods: A total of 279 bladder specimens (137 tumors, 107 adjacent normal tissues and 35 healthy samples) were included. Total RNA was extracted, reverse transcribed, and KLK13 expression was assessed by quantitative real-time PCR. Results: KLK13 expression is significantly increased in bladder tumors compared to normal adjacent epithelium. However, reduced KLK13 expression is correlated with disease aggressiveness, including higher tumor stage and grade, and high-risk TaT1 tumors according to the EORTC stratification. Moreover, Kaplan-Meier and Cox regression analysis highlighted the prognostic value of the reduced KLK13 expression for the prediction of TaT1 patients' recurrence and shorter disease-free survival following TURBT. Finally, the combination of KLK13 expression with EORTC-risk stratification results to an improved prediction of TaT1 patients' outcome. Conclusion: This first clinical study of KLK13 in BlCa reveals its deregulated expression in bladder tumors and highlights KLK13 as a promising marker for improving TaT1 patients' prognosis following treatment. [ABSTRACT FROM AUTHOR]

The family of kallikrein-related peptidases (KLKs) has been identified in a variety of immunolabeled human tissue sections, but no previous study has experimentally confirmed their presence in the human neutrophil. We have investigated the expression and bioregulation of particular KLKs in the human neutrophil and, in addition, examined whether stimulation by a kinin B[sub 1] receptor (B1R) agonist or fMet-Leu-Phe (fMLP) induces their secretion. Western blot analysis of neutrophil homogenates indicated that the MM of the KLKs ranged from 27 to 50 kDa. RT-PCR showed that blood neutrophils expressed only KLK1, KLK4, KLK10, KLK13, KLK14 and KLK15 mRNAs, whereas the non-differentiated HL-60 cells expressed most of them, with exception of KLK3 and KLK7. Nevertheless, mRNAs for KLK2, KLK5, KLK6 and KLK9 that were previously undetectable appeared after challenging with a mixture of cytokines. Both kinin B[sub 1]R agonist and fMLP induced secretion of KLK1, KLK6, KLK10, KLK13 and KLK14 into the culture medium in similar amounts, whereas the B[sub 1]R agonist caused the release of lower amounts of KLK2, KLK4 and KLK5. When secreted, the differing proteolytic activity of KLKs provides the human neutrophil with a multifunctional enzymatic capacity supporting a new dimension for its role in human disorders of diverse etiology. [ABSTRACT FROM AUTHOR]

Given that 1.3 million new cases of breast cancer are universally registered among women and approximately 36 % of the patients die annually, the revelation of new predictive markers for treatment efficiency is of vital importance. Recently, our group has depicted that KLK4, KLK5, and KLK14 are differentially expressed in breast carcinoma. The objective of this study was to determine and investigate the expression pattern of the KLK4, KLK5, and KLK14 genes in breast cancer cells after treatment with established chemotherapeutic agents. We evaluated these genes' expression after treatment of the BT-20 cells with epirubicin, docetaxel and methotrexate, determining their cytotoxic effect by MTT and trypan blue assays. The relative quantification of genes' mRNA levels was performed by using the SYBR Green® chemistry, and the HPRT1 served as an endogenous control gene. The drugs triggered apoptosis in treated cells and induced deregulations in the expression of the above KLKs. The most significant alterations were a 12-fold and tenfold increase of KLK5 in docetaxel and methotrexate-treated cells, respectively, while the KLK4 levels decreased by ten-fold in epirubicin, five-fold in docetaxel and twenty-fold in methotrexate treated-cells, compared to the untreated ones. In the case of KLK14 levels, a twofold increase in epirubicin and threefold decrease in methotrexate-treated cells were observed. Present significant alterations in the expression pattern of KLK4, KLK5, and KLK14 could comprise an initial stage for predicting chemotherapy response in breast cancer and should be further investigated as predictive markers in the future. [ABSTRACT FROM AUTHOR]

Gastric cancer constitutes one of the most common neoplasms globally. Kallikrein-related peptidases have attracted interest as potential tumor markers and future targets for novel cancer therapeutics. We have recently reported KLK13 clinical importance as a favorable prognostic biomarker for gastric cancer patients' survival. By aiming to explore how the molecular profile of KLK13 is modified in stomach cancer cells treated with antineoplastic drugs, we examined, for the first time, the mRNA alterations of this gene following gastric cancer cells' exposure to the prominent chemotherapeutic substances epirubicin, oxaliplatin, or methotrexate. The antiproliferative effects of these agents, on AGS cells' growth, were determined by the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide and trypan blue assays. Total RNA, isolated from the harvested cells, was reverse-transcribed to cDNA. KLK13 levels were quantified via real-time PCR using the SYBR Green chemistry. The relative changes of KLK13 expression were calculated with the comparative C (2) method. Distinct KLK13 profiles resulted from AGS cells' incubation with epirubicin or methotrexate for 24, 36, and 48 h. KLK13 expression increased in a time-dependent manner up to 5.70 times (for epirubicin) or 5.76 times (for methotrexate) at 48 h compared with the corresponding untreated cells. According to our results, KLK13 expression is implicated in the molecular pathways that are triggered after administration of anticancer agents on gastric cancer cells. Moreover, our data support the possibility that KLK13 may be exploited as a future molecular predictor of gastric cancer cells' response to chemotherapy. [ABSTRACT FROM AUTHOR]

Tissue kallikrein ( KLK1) and the kallikrein-related peptidase ( KLK2–15) genes encode for a subgroup of 15 homologous secreted serine proteases possessing numerous physiological roles, such as the regulation of blood pressure, hormone processing and tissue remodeling. The expression of KLKs is detected in a broad spectrum of human tissues where it has been found to be regulated mainly by steroids hormones. The aberrant expression of KLKs, presented in many human malignancies, highlights the significance of this gene family for early diagnosis, prognosis and monitoring of cancer patients, as it is strongly emphasized by the routine use of PSA (KLK3) for prostate cancer management. Here, we review the presently known data regarding the role of KLKs as cancer biomarkers, giving emphasis on novel information about the subject. [ABSTRACT FROM AUTHOR]

Several members of the human tissue kallikrein-related peptidase (KLK) family are emerging cancer biomarkers. The aim of this study was to analyse the expression of a panel of KLKs in colorectal cancer and to find out if the multiparametric combination of them can increase the accuracy of prediction of patients survival beyond the traditional clinical information. Nine KLKs (KLK5-8, KLK10, KLK11, KLK13-15) were measured using ELISA assays in cytosolic extracts of 122 colon cancer tissues and their nearby normal mucosa, obtained during surgery. The mean levels of almost all KLKs in tumour tissues were significantly different from their counterparts of normal tissue (P<0.0001). KLK 5, 6, 7, 13, 14 were significantly associated with overall survival in univariate analysis, but after adjusting for age, TNM and differentiation stage, only KLK5 (HR: 1.24 (95% CI: 1.05-1.47)), KLK7 (HR: 1.57 (95% CI: 1.04-2.37)) and KLK14 (HR: 1.43 (95% CI: 1.05-1.94)) remained significant. Addition of a panel of selected KLK markers to clinical parameters gave an increment in AUC of 0.86 beyond the clinical factors at year 1, showing that it can increase the accuracy of prediction of overall survival beyond the traditional clinical information, particularly the short-term (1 year) survival after surgery. [ABSTRACT FROM AUTHOR]