ADAMTS-8 and kallikrein-related peptidases 10 and 5 proteases also have a tumor suppression role

Abstract

Proteases are essential for homeostasis, and their primary function is proteolytic in extracellular and intracellular compartments. The deregulation of expression, abundance, and activity of proteases has been related to several pathologies, including cancer. This deregulation contributes to their pro-tumorigenic activity since they participate in the degradation of extracellular matrix components and adhesion molecules, and the activation of growth factors. However, some proteases, such as ADAM metallopeptidase with thrombospondin type 1 motif 8 and kallikrein-related peptidases 5 and 10, have emerged as tumor suppressors due to their antitumoral actions in specific cancer contexts. In this article, we discuss the antitumoral effects of ADAM metallopeptidase with thrombospondin type 1 motif 8, kallikrein-related peptidases 5 and 10 that have been described to date, suggesting their potential use as novel biomarkers and therapeutic targets in cancer.

Key Words: ADAM metallopeptidase with thrombospondin type 1 motif 8; Kallikrein-related peptidases 5; Kallikrein-related peptidases 10; Kallikreins; Proteases; Tumor suppressor

Core Tip: In this article, we explore the published information on two proteases of the kallikrein family, kallikrein-related peptidases 5 and 10, and one metallopeptidase with a thrombospondin motif, ADAM metallopeptidase with thrombospondin type 1 motif 8, which are suggested to be both tumor suppressors and protumoral factors, depending on cancer context and stage.

INTRODUCTION

Proteases belong to a large group of proteins with complex enzymatic functions, mainly performing the hydrolysis of peptides between amino acids in a protein, a process known as proteolysis. Living organisms must break down proteins to obtain amino acid units and synthesize the necessary biomolecules. Some proteins are catalytically inactive and are activated through proteolytic cleavage, revealing an important mechanism of biological regulation by proteases. Cell growth and remodeling processes also require protease participation[1]. In general, proteases are parts of molecular mechanisms that prevent protein accumulation; activate or inhibit the functions of their target proteins; change the localization of some proteins; regulate the release and/or activation of cytokines, growth factors, and peptide hormones; and facilitate cell adhesion and migration[2]. At the physiological level, the participation of proteases is relevant in embryonic development, morphogenesis, skin homeostasis, blood coagulation cascade, and intestinal function[3]. When the protein homeostasis regulated by proteases is inadequate, the organism can develop diseases, such as malignant tumors[1].

Proteases can be classified based on the functional groups located in their active sites, the type of reaction they catalyze, the nature and chemical properties of their catalytic sites, the structure of the protease, and their activation mechanisms. Human proteases include cysteine proteases, serine proteases, metalloproteases, aspartic proteases, and threonine proteases[1]. In humans, 24 matrix metalloproteinase proteins, 21 disintegrin and metalloproteinase (ADAM) proteins, and 19 disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteins have been identified[4-6].

Histidine, glutamic acid, aspartic acid, and lysine are the most common residues found in the active site of metalloproteases[5]. Metalloproteases are characterized by having a metallic ion (Zn²⁺, Co²⁺, Mn²⁺, or Ni²⁺) coordinated with the amino acid side-chains and a single water molecule at their catalytic site[5]. The zinc-dependent metalloproteinases comprise a superfamily of proteinases, including matrix metalloproteinase proteins, ADAM, and ADAMTS. The ADAM protease structure contains a signal peptide, a pro-domain, a catalytic domain, a disintegrin domain, a cysteine-rich domain, an epidermal growth factor–like domain, a transmembrane domain, and a cytoplasmic tail. ADAMTS differs in the inclusion of a spacer domain and a thrombospondin type-like repeat domain, and the absence of a transmembrane domain[6,7]. In contrast, the active site of serine proteases involves a catalytic triad of serine, histidine, and aspartate[3].

The participation of proteases in cancer has been described as pro-tumorigenic for several years because the target proteins of many proteases are components of the extracellular matrix (ECM), promoting its remodeling and, subsequently, cell migration, invasion, and metastasis, one crucial hallmark of cancer[8-10]. However, some studies suggest that, depending on the cellular context and stage of cancer progression, some proteases could act as tumor suppressors[11]. This work discusses the roles of one metalloprotease [ADAM metallopeptidase with thrombospondin type 1 motif 8 (ADAMTS-8)] and two serine proteases [kallikrein-related peptidases (KLK) 5 and KLK10] in the context of cancer.

ADAMTS-8, A METALLOPROTEASE WITH ANTITUMORAL ACTIVITY

The protease ADAMTS-8 is mainly found in the extracellular space, with predominant expression in the lung and heart[7]. Similar to other members of the ADAMTS family, ADAMTS-8 is produced as a zymogen that consists of a pre-domain (a signal peptide) and a pro-domain that is cleaved by proprotein convertases such as furin, resulting in a mature protein[6]. The ADAMTS protein family includes 19 members and is characterized by ECM metalloproteases with at least one thrombospondin 1-like motif (TSR)[12]. ADAMTS-8 is composed of its respective pre- and pro-domains, a metalloproteinase domain, a disintegrin domain, and an auxiliary domain that comprises a central TSR, a cysteine-rich domain, a cysteine-free spacer domain, and a terminal TSR (Figure 1)[6].

Figure 1 Schematic representation of ADAM metallopeptidase with thrombospondin type 1 motif 8 and distribution in the human body under normal and cancer conditions[93]. The blue color represents healthy conditions, and the orange color represents tumor conditions. A higher intensity of color correlated with a higher expression of ADAM metallopeptidase with thrombospondin type 1 motif 8 (ADAMTS-8) in the indicated organ. A: Protein structure of ADAMTS-8; B: Schema modified of GEPIA web server based on expression of ADAMTS-8 in the human body. Citation: Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 2017; 45: W98-W102. Copyright ©The Authors 2025. Published by Oxford University Press. (https://academic.oup.com/pages/open-research/open-access). ADAMTS-8: ADAM metallopeptidase with thrombospondin type 1 motif 8; TPM: Transcripts per million.

Interestingly, ADAMTS-8 has been implicated in placental development and function, exhibiting strong placental expression in the early stages of gestation[13], and plays a crucial role in the remodeling of the ECM of stromal cells to decidua during pregnancy[14] and in the inhibition of angiogenesis through the inhibition of vascular endothelial growth factor[15]. The tissue inhibitor of metalloproteinase 3 can inhibit the proteolytic activity of ADAMTS-8[16].

In the context of cancer, ADAMTS-8 exhibits a negative correlation with various types of cancer. For instance, the downregulation of ADAMTS-8 has been reported in brain tumors compared to normal tissue[17]. The overexpression of ADAMTS-8 reduces the migration, viability, invasion, and epithelial-mesenchymal transition of glioma cells and reduces brain tumor growth in vivo. Furthermore, the high expression of ADAMTS-8 in primary glioma patients is associated with improved survival compared to patients with low expression and high-grade gliomas[18].

In the case of breast cancer (BC), several studies have found that ADAMTS-8 can have an antitumoral function. Hence, a low expression of ADAMTS-8 in early-stage BC patients correlates with an increased propensity to develop metastasis[19]. Likewise, ADAMTS-8 expression has been found to be lower in tissue derived from BC patients than in adjacent non-tumoral tissue. Additionally, an increase of ADAMTS-8 expression can inhibit proliferation and invasion of BC cells (MDA-MB-231) and induce apoptosis. These results are consistent with those found in in vivo experiments, where the overexpression of ADAMTS-8 reduced tumor growth, suggesting its possible activity as a tumor suppressor[20]. Moreover, ADAMTS-8 overexpression induced cell-cycle arrest, inhibiting BC cell (MDA-MB-231 and BT549) proliferation, migration, and invasion in vitro. ADAMTS-8 expression was higher in normal tissues than in breast tumor tissues by a mechanism associated with ADAMTS-8 gene promoter methylation[21]. In particular, in samples of patients with invasive ductal carcinoma (IDC) human epidermal growth factor receptor 2-positive (HER2+), the level of ADAMTS-8 was higher than in samples with IDC HER2- and in samples from breast fibroadenoma (non-cancerous tissue), suggesting that a positive relationship between ADAMTS-8 and HER2 expression could have a protumoral role in IDC[22].

Other studies have also indicated that the ADAMTS-8 promoter is methylated in non-small-cell lung tumors (NSCLC), glioblastoma, esophageal squamous cell cancer (ESCC), gastric cancer (GC), and colorectal carcinomas (CRC). Thereby, ADAMTS-8 is frequently downregulated in several cancer types via the methylation of the ADAMTS-8 promoter[17,23-25]. At the functional level, ADAMTS-8 typically acts as a tumor suppressor by inhibiting proliferation, migration, and invasion, inducing apoptosis and growth arrest in several tumors, including hepatocellular carcinoma[24,26], CRC[24,27], ESCC[24,28], and NSCLC[24,26]. Despite the downregulation of ADAMTS-8 and its effect as a negative modulator of cancer hallmarks in different cancer types, its molecular target and action mechanisms are still unclear.

KALLIKREIN PROTEASES

KLKs are members of another protease family. The KLK gene family comprises a cluster of 15 genes on chromosome 19q13.4, which have five conserved exons but differ in non-coding regions and the length of their intron sequences. Hence, the KLK family comprises 15 serine endopeptidases involved in various physiological processes[29]. The expression of KLK can be modulated by steroid hormones, such as androgens, progestins, and estrogens, as well as vitamin D, thyroid hormone, retinoic acid, epigenetic mechanisms, and microenvironment components, among others[30]. KLK genes encode a single-chain pre-pro-proteinase that contains a chymotrypsin or trypsin-like catalytic domain of 224-237 residues, having histidine, aspartic acid, and serine (the catalytic triad) in their catalytic domain[30,31]. All KLKs are synthesized as inactive pre-pro-enzymes and are translocated as inactive zymogens into the endoplasmic reticulum upon removal of the signal peptide. After secretion into the extracellular space, the pro-KLKs are activated by proteolytic release of a pro-peptide from the N-terminus, typically 4-9 amino acids in length. It has been proposed that KLKs can activate themselves[29].

The repertoire of substrates of the human KLK family is vast and still expanding, including hormones, growth factors, ECM proteins, cell receptors, adhesion molecules, and even other types of proteolytic enzymes[32]. The KLK family is involved in many pathological processes, such as inflammation, hypertension, and cancer[32]. In cancer, the KLK family has been related to malignancy promotion but also to the tumor suppression function[11,33-35]. Two KLK protease family members emerging as potential tumor suppressors are KLK10 and KLK5, which are discussed below.

KLK10: THE FIRST KALLIKREIN CONSIDERED AS A TUMOR SUPPRESSOR

The protein KLK10 is encoded by the KLK10 gene, also known as the normal epithelial cell-specific-1 gene (Figure 2). This protease has 276 amino acids, is N-glycosylated at Asn₃₉ for its secretion as a pro-enzyme, and is activated through cleavage at the position Arg₄₂. KLK10 contains a trypsin-like serine domain as a central domain and is considered a member of the chymotrypsin family of serine S1A peptidases. KLK10 is mainly found in the extracellular space[30,31]. A high expression of KLK10 is detected in the breast, ovary, testis, and prostate[29]. Hormonal stimuli, such as estrogen, androgen, and progestin, can modulate KLK10 expression[36].

Figure 2 Schematic representation of kallikrein-related peptidases 10 and 5 and distribution in the human body in normal and cancer conditions[93]. The blue color represents healthy conditions, and the orange color represents tumor conditions. A higher intensity of color correlated with a higher expression of kallikrein-related peptidases (KLK) 10 or KLK5 in the indicated organ. A: KLK10 and KLK5 gene structure. Both genes have five coding exons (gray boxes) and one non-coding exon (blue boxes). The length (in base pairs) of exons and introns is indicated inside and outside the boxes, respectively. The black row represents the position of the start codon, and the orange row indicates the stop codon’s position; B: Protein structure of KLK10 and KLK5; C: Schema modified of GEPIA web server for the expression of KLK10 and KLK5 in the human body. Citation: Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 2017; 45: W98-W102. Copyright ©The Authors 2025. Published by Oxford University Press. (https://academic.oup.com/pages/open-research/open-access). KLK: Kallikrein-related peptidases; TPM: Transcripts per million.

KLK10’s role as a tumor suppressor has been evidenced in some cancer types, where the expression of this protease is downregulated (Table 1), and the mechanism responsible seems to be associated with DNA methylation. For instance, the downregulation of KLK10 has been related to hypermethylation in BC and prostate cancer (PCa)[37]. In PCa, overexpression of KLK10 reduces tumor proliferation and glucose metabolism while increasing apoptosis[38] and enhancing sensitivity to radiotherapy[39]. In addition, the reduction or loss of KLK10 mRNA expression correlates with the methylation of KLK10 in CpG islands observed in acute lymphoblastic leukemia[40,41], GC[42], and NSCLC[43].

Table 1 Expression of KLK10 in some types of cancers.

Cancer	Expression of KLK10 in the tumor compared with non-tumor conditions	Ref.
Breast cancer	Expression depends on stage, grade, and metastasis	[37,44,46-48]
Gastric cancer	Expression depends on stage, grade, and metastasis	[42,49,94]
Prostate cancer	Decreased	[37,38]
Esophageal cancer	Decreased	[52]
Acute lymphoblastic leukemia	Decreased	[40,41]
Testicular cancer	Decreased	[95]
Ovarian cancer	Decreased	[37]
Cutaneous melanoma	Increased	[55]
Colorectal cancer	Increased	[50,51]
Colon cancer	Increased	[96]
Pancreatic cancer	Increased	[53,54]

Although KLK10 was identified as the first serine protease with an antitumoral function in BC, KLK10 seems to play a dual role in the tumorigenesis of mammary tissue. First, decreased KLK10 expression in tumor cell lines and primary breast tumors has been associated with its gene hypermethylation[33]. Furthermore, KLK10 expression is higher in normal breast tissue and benign lesions than in BC tissue, suggesting that KLK10 expression may be a molecular marker of BC[44]. In addition, a decrease in KLK10 expression has been reported in ductal carcinoma in situ and is associated with a high risk of invasive carcinoma[45]. Nevertheless, in BC trastuzumab-resistant cells, KLK10 was found to be elevated, displaying a worse prognosis than in patients with a lower expression of KLK10[46]. A similar scenario occurs in triple-negative BC, since high levels of KLK10 are related to lower survival[47,48]. These studies suggest that KLK10 has a dual role in BC tumorigenesis depending on the subtype of BC.

Protumoral activity of KLK10 has also been reported in different cancer types (Table 1). In GC, KLK10 expression promotes trastuzumab resistance by activating the phosphatidylinositol 3-kinase/protein kinase B pathway[49]. Another study showed that silencing KLK10 reduces cell viability and glucose metabolism and promotes apoptosis in CRC[50]. In this context, high expression of KLK10 reduces survival, mainly in patients with grade I and II cancers[51]. A higher KLK10 expression correlates with chemotherapy resistance using cisplatin in ESCC[52]. Altered KLK10 expression has also been associated with the development of pancreatic adenocarcinomas[53,54] and melanomas[55]. In all these cancers, high KLK10 expression is correlated with poorer survival outcomes. Thus, KLK10 acts as a tumor suppressor but also has a protumoral function depending on the cancer type, subtype, and progression stage.

KLK5: A SERINE PROTEASE WITH DUAL ACTION IN CANCER

KLK5 is a protein of 293 amino acids that requires glycosylation on Asn₆₉ for its secretion (Figure 2)[31] and is located in the cytosol, the epidermal lamellar body[56], extracellular space, and secretory granules[57]. The expression of KLK5 is upregulated by estrogens and progestins[58] and inhibited by Zn²⁺[59]. KLK5 is detected in the skin and in all stratified epithelia[34,60] and is involved in skin desquamation during epidermal differentiation[61,62]. The breast, brain, and testis also express high levels of this protease[29].

KLK5 can self-activate, promote the activation of other KLKs (e.g., KLK7), and cleave ECM components (collagen, fibronectin, and laminin)[32,62]. The expression of KLK5 is lost in advanced-stage human skin cancer[63], but KLK5 downregulation has also been reported in hormone-dependent tumors[35,64-66] and tumors of the reproductive system[34,64,67,68].

In particular, KLK5 plays a role as a tumor suppressor in PCa, since KLK5 expression is decreased in these tumors by androgens and a higher KLK5 expression represents a better prognosis[35,58]. In vaginal tumors, KLK5 deficiency increases resistance to apoptosis[34]. In testicular cancer tissue, KLK5 expression is lower than in early-stage tumors[67], while in ovarian cancer (OC) cell lines, the co-expression of KLK5, 6, and 10 decreased colony formation in soft agar and tumorigenicity in nude mice[69].

In BC, KLK5 expression decreases in all subtypes compared to normal tissue[70-72]. It has been suggested that the oncogene GNA13 negatively regulates KLK5 gene transcription, promoting BC progression[73]. In triple-negative BC cells, overexpression of KLK5 suppresses key epithelial-mesenchymal transition genes, decreasing malignancy[66]. However, it has been suggested that the co-expression of KLK5 with the DSG1 and DSG3 genes is associated with the progression of triple-negative BC[65]. In this BC subtype, the silencing of the KLK5/7 and MFGE8 genes restored sensitivity to selective cyclooxygenase-2 inhibitors, such as celecoxib, significantly reducing primary tumor growth[74]. Additionally, high concentrations of the KLK5 protein have been found in the serum of patients with OC and BC compared with levels in the serum of healthy individuals[75]. These data indicate a duality of KLK5 function in mammary malignant tumorigenesis.

In contrast, KLK5 Levels are increased in uterine cervical cancer[76] and OC, increasing invasion and chemoresistance[77-80]. In gastric adenocarcinoma, patients with higher KLK5 expression were found to have shorter overall survival, enhanced tumor invasion, and nodal metastasis[81]. KLK5 is overexpressed and acts as a pro-tumorigenic factor in lung adenocarcinoma[82,83]. In primary bladder carcinoma, the expression of KLK5 promotes cell migration and invasion[84]. These investigations indicate a pro-tumorigenic role of KLK5 for some cancer types.

Furthermore, as in BC, in oral squamous cell carcinoma, KLK5 has both pro- and antitumor functions. Whereas the loss of KLK5 and KLK7 Leads to a poor clinical prognosis[85,86], the overexpression of KLK5 correlates with metastasis and the formation of more aggressive tumors[87-89] and, consequently, the silencing of KLK5 reduces tumor inflammatory infiltrate[90]. These data suggest that other molecular pathways may modulate the pro- and antitumor activity of KLK5 depending on cancer type (Table 2).

Table 2 Expression of KLK5 in some types of cancer.

Cancer	Expression of KLK5 in the tumor compared with non-tumor conditions	Ref.
Breast cancer	Expression depends on stage, grade, and metastasis	[65,66,70,74]
Oral squamous cell carcinoma	Expression depends on stage, grade, and metastasis	[88,89,97]
Vaginal carcinogenesis	Decreased	[34]
Prostate cancer	Decreased	[35]
Testicular cancer	Decreased	[67]
Ovarian cancer	Increased	[77,68]
Skin tumorigenesis	Increased	[61]
Urinary bladder carcinoma cells	Increased	[84]
Uterine cervical cancer	Increased	[76]
Lung cancer	Increased	[83]
Gastric adenocarcinoma	Increased	[81]

ADAMTS-8, KLK10, AND KLK5 AS POTENTIAL BIOMARKERS AND THERAPEUTIC TARGETS FOR CANCER TREATMENT

Tissue remodeling is the reorganization or renewal of tissue structures that can occur during organ development and functional maturity, during wound healing responses, or as a pathogenic process in diseases such as arthritis, asthma, and cancer[1,2]. For this modification, changes in cell function and ECM structure as well as the presence and activation of differential proteases are necessary[2]. Proteases have been implicated in oncogenesis by regulating the proliferation of cancer cells, as extensive proliferation is often accompanied by tissue remodeling. In this context, proteases play critical roles by modulating cell–cell and cell-ECM communication[8,9].

In general terms, proteases have been associated with protumor activity within the tumor microenvironment, thereby enhancing cancer progression. However, evidence indicating that some proteases can have antitumor activities is increasing. ADAMTS-8, KLK10, and KLK5 are three examples of proteases with antitumor functions in some malignant neoplasms (Figure 3). ADAMTS proteins have been reported to exhibit both antitumor and protumor effects, partly attributed to their dual role in angiogenesis[15,17,91]. However, ADAMTS-8 is primarily recognized as an antitumor protease. For instance, low expression of ADAMTS-8 has been associated with a poor prognosis in hepatocellular carcinoma patients, as there is evidence that basal levels of ADAMTS-8 inhibit proliferation and favor apoptosis[26]. It has been suggested that the ADAMTS-8 protease may carry out its antitumor functions by regulating the EGFR/ERK signaling pathway axis in certain cancers[21,24,26]. It has also been reported that ADAMTS-8 exhibits aggrecanase activity, which is involved in the degradation of the ECM in human articular cartilage, but its behavior in a cancer context is still unknown[7,12]. Depending on the cellular context and tumor malignancy, the enzymatic activities of ADAMTS-8 may be modulated differentially, causing it to have a dual role in BC.

Figure 3 Hallmarks of cancer associated with ADAM metallopeptidase with thrombospondin type 1 motif 8, kallikrein-related peptidases 10 and 5 proteases. Orange arrow indicates promotion, and the black line indicates inhibition. Both lines (orange and black) indicate the association between a hallmark of cancer and these proteases, depending on the cellular context. ADAMTS-8: ADAM metallopeptidase with thrombospondin type 1 motif 8; KLK: Kallikrein-related peptidases.

Regarding KLK5/10, although they are two members of the KLK family, they differ in their tissue distribution and have different mechanisms of action and participation in physiological processes. Studies to establish connections between KLK10 and other proteases, including KLK5 and ADAMTS-8, especially in pathological contexts such as cancer, are still limited. Structurally, KLK5 and KLK10 are similar, but human KLK10 has a unique longer N-terminus, which may confer a differential role in the same cellular context, such as BC[92]. The oncogenic function of these proteases has been associated with the regulation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway in specific contexts[46,49,50,52]. Nevertheless, these proteases seem to have an antitumor role in several cancer types. For example, KLK5 can act as a tumor suppressor by repressing the mevalonate pathway in BC[66]. The targets and molecular mechanisms of these proteases, which function as either oncoproteins or tumor suppressors, have not been elucidated to date.

Interestingly, the downregulation of these three proteases in cancer is associated with DNA hypermethylation, a mechanism commonly employed by cancerous cells to silence several tumor suppressors. The tumor suppressor activity of these proteases probably occurs mainly in the early stages of cancer rather than in later stages. The molecular profile of each cancerous tissue type may also define the pro- or antitumor activity of these proteases. Because KLK5 and KLK10 can act as oncoproteins or tumor suppressors, depending on cancer type, these proteases display a dual role in BC. Since mammary malignant tumors are considered a neoplasia collection due to their high tissue and molecular heterogeneity, it is possible to understand that the activity of these KLKs is related to the stage and subtype of BC cells.

Therefore, the function of these proteases as tumor suppressors depends on the cancer stage or metastasis conditions, and they can be turned on or off depending on the tumor microenvironment (Table 3). Together, these data highlight that ADAMTS-8, KLK10, and KLK5 proteases can be considered bona fide tumor suppressors in some cancers.

Table 3 ADAM metallopeptidase with thrombospondin type 1 motif 8, kallikrein-related peptidases 10 and 5 in some human cancers.

Cancer	Expression of ADAMTS-8	Expression of KLK10	Expression of KLK5
Breast cancer	1	1	1
Prostate cancer	-	-	2
Testicular cancer	-	2	2
Vaginal cancer	-	-	2
Ovarian cancer	-	2	3
Gastric cancer	2	1	3
Brain cancer	2	-	-
Lung cancer	2	2	-
Colorectal cancer	2	3	-
Esophageal squamous cell carcinoma	2	-	-
Hepatocellular carcinoma	2	-	-
Esophageal cancer	-	2	-
Acute lymphoblastic leukemia	-	2	-
Skin cancer	-	3	3
Colon cancer	-	3	-
Pancreatic cancer	-	3	-
Oral squamous cell carcinoma	-	-	1
Urinary bladder carcinoma cells	-	-	3

¹Indicates dual function.

²Indicates downregulation with function as a tumor suppressor.

³Indicates overexpression with protumoral properties.

Despite these findings, the proteolytic targets of these proteases are not entirely known, and consequently, no common substrates have been identified for these proteases. However, the co-expression of KLK5 and KLK10 has been found in tumor cells of squamous cell carcinoma[89], suggesting that they may function cooperatively, participating in a common pathway and possibly sharing some molecular targets. Some tumor-suppressing actions of these proteases may likely occur in a proteolytic activity-independent manner. Therefore, the molecular mechanisms implicated in the tumor suppressor actions of these proteases remain to be investigated.

The mechanisms implicated in the dual role, both pro- and antitumor, of these proteases in a cell context–dependent manner are not clear. Nevertheless, it is known that, in cancer, there is a loss of fine control in the expression of these proteases. Additionally, the deregulation of these proteases may occur in terms of their abundance and activation. Hence, the levels and activity of their inhibitors, activators, and specific substrates, as well as the potential crosstalk between them, may contribute to their ultimate function, promoting or inhibiting tumor progression in particular contexts of cancer.

CONCLUSION

In conclusion, some proteases exhibit tumor suppressor activity. ADAMTS-8, KLK5, and KLK10 exhibit antitumor activity in malignant tumors and may serve as biomarkers and therapeutic targets in cancer. However, further research is required to detect these proteases in liquid biopsies and to develop assays for their detection. Further studies are also needed to elucidate the mechanisms of action, expression profiles, and activities of these proteases during the progression of specific cancers in order to design novel therapeutic strategies based on these proteases.

ACKNOWLEDGEMENTS

Eva G Palacios Serrato, Karen H Medina Abreu and Enrique Oropeza Martínez are postgraduate fellowship recipients from Secretaría de Ciencia, Humanidades, Tecnología e Innovación. We thank Norma Angélica Lira-Rodríguez, and Siankaan Harlem Ziu Lopez Mignon for their help with the figures.