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Biochimica et Biophysica Acta 1776 (2007) 22–31 www.elsevier.com/locate/bbacan

Review Tissue proteolytic cascade pathways in normal physiology and cancer ⁎ ⁎ Georgios Pampalakis , Georgia Sotiropoulou

Department of Pharmacy, University of Patras, Rion-Patras 26500, Greece

Received 14 April 2007; received in revised form 2 June 2007; accepted 4 June 2007 Available online 14 June 2007

Abstract

Human tissue (KLKs or kallikrein-related peptidases) are a subgroup of extracellular proteases that act on a wide variety of physiological substrates, while they display aberrant expression patterns in certain types of cancer. Differential expression patterns lead to the exploitation of these as new cancer biomarkers for hormone-dependent malignancies, in particular. The prostate-specific antigen or kallikrein-related peptidase 3 (PSA/KLK3) is an established tumor marker for the diagnosis and monitoring of prostate cancer. It is well documented that specific KLK are co-expressed in tissues and in various pathologies suggesting their participation in complex proteolytic cascades. Here, we review the currently established knowledge on the involvement of KLK proteolytic cascades in the regulation of physiological and pathological processes in prostate tissue and in skin. It is well established that the activity of KLKs is often regulated by auto-activation and subsequent autolytic internal cleavage leading to enzymatic inactivation, as well as by inhibitory serpins or by allosteric inhibition by zinc ions. Redistribution of zinc ions and alterations in their concentration due to physiological or pathological reasons activates specific KLKs initiating the kallikrein cascade(s). Recent studies on kallikrein substrate specificity allowed for the construction of a kallikrein interaction network involved in semen liquefaction and prostate cancer, as well as in skin pathologies, such as skin desquamation, psoriasis and cancer. Furthermore, we discuss the crosstalks between known proteolytic pathways and the kallikrein cascades, with emphasis on the activation of and its implications in prostate cancer. These findings may have clinical implications for the underlying molecular mechanism and management of cancer and other disorders in which KLK activity is elevated. © 2007 Elsevier B.V. All rights reserved.

Keywords: Human tissue kallikreins; Proteolytic cascades; Prostate cancer; Semen liquefaction; Skin desquamation; Skin cancer

Contents

1. Introduction ...... 23 2. A tissue kallikrein cascade regulates semen liquefaction ...... 24 3. Involvement of a tissue kallikrein cascade in prostate cancer ...... 25 4. The role of tissue kallikrein cascade in skin desquamation ...... 26 5. Tissue kallikreins are involved in psoriasis and skin cancer...... 28 6. Tissue kallikrein cascades in other tissues...... 28 7. Conclusions ...... 28 References ...... 28

⁎ Corresponding authors. Tel.: +30 2610 969939, tel./fax: +30 2610 969940. E-mail addresses: [email protected] (G. Pampalakis), [email protected] (G. Sotiropoulou).

0304-419X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2007.06.001 Author's personal copy

G. Pampalakis, G. Sotiropoulou / Biochimica et Biophysica Acta 1776 (2007) 22–31 23

1. Introduction Multiple transcriptional and post-transcriptional mechanisms control the expression, consequently, the proteolytic activity of Proteolytic cascades are implicated in many physiological tissue kallikreins [reviewed in [2,8]]. At the level of transcrip- processes, such as blood , food digestion, apoptosis tion, alternative splicing results in either the production of and others [1]. A proteolytic cascade initiates when an activated multiple splice variants that encode for truncated proteins or do protease cleaves and activates other protease zymogens that not encode for any predicted sequences [reviewed in [7]]. function downstream. This leads to the rapid amplification of Interestingly, distinct KLK variants display tumor-specific the original signal. Serine proteases constitute a subgroup of expression as was demonstrated for KLK5 [9–11], KLK7 [9], proteases known to participate in proteolytic cascades [1]. KLK8 [12] and KLK13 [13]. On the other hand, steroid Human kallikreins, in particular, are divided into two hormones are considered as the primary regulatory mechanism categories: Plasma kallikreins and tissue kallikreins [2]. Plasma of tissue kallikrein expression [reviewed in [8]]. However, kallikrein or Fletcher factor is encoded by a single gene recent data implicated genomic DNA methylation in the localized on human 4q35 [3,4]. This gene is regulation of aberrant tissue kallikrein expression observed in composed of 15 exons and encodes for an that releases tumor cells, as was described for KLK6 in breast cancer [14] and the bioactive peptide bradykinin from high molecular weight for KLK10 in prostate [15], breast [15,16], ovarian tumors [15] kininogen (HMWK). Tissue kallikreins are the largest group of and in acute lymphoblastic leukemia [17]. The mRNAs serine proteases in the and are localized in encoding for tissue kallikreins are translated as inactive tandem on human chromosome 19q13.4. Fig. 1 is a schematic zymogens (preproKLK) that are either autoactivated or activated presentation of the human tissue kallikrein locus, which is now by other KLKs or different proteases. The enzymatic activity of known to consist of 15 genes [2] and one pseudogene [5]. mature (active) KLKs is further regulated by physiological According to the nomenclature suggested recently for human inhibitors or allosterically by ions, such as Zn2+ [2]. tissue kallikreins, the gene is referred to as KLK followed by the This review focuses on known proteolytic cascades formed appropriate number and the protein as KLK followed by the by enzymaticaly active KLKs. It is known that several KLK- appropriate number [6]. Most KLK genes contain one or more encoding genes are co-expressed in specific tissues and they are untranslated exons and five coding exons with identical exon– co-ordinately disregulated in certain pathologies. Therefore, it is intron phases, while their 3′ untranslated region is usually considered that multiple KLKs are involved in proteolytic variable, giving rise to mRNA variants with differing sequence cascade pathways that might be operated entirely by KLKs or lengths, that all encode for identical full-length proteins [7]. may also involve the action of other proteases. Human KLKs Tissue kallikrein genes all encode for serine proteases with are secreted suggesting that their biological role is either -like (KLK1, KLK2, KLK4, KLK5, KLK6, related to their ability to cleave one or more substrates. KLK8, KLK10, KLK11, KLK12, KLK13, KLK14, KLK15) Recently, in vitro studies suggested that KLKs are able to or -like (KLK3, KLK7, KLK9) activity [2]. process growth factor binding proteins and cleave components

Fig. 1. The human tissue kallikrein gene cluster. The tissue kallikrein genes (KLK) are localized in tandem on human chromosome 19q13.4 and constitute a subfamily of 15 members [2]. The aim of each arrow indicates the direction of transcription of the corresponding gene. Most KLK genes contain one or two untranslated 5′ exons (shown in white boxes). The encoded enzymes are synthesized as inactive preproKLKs. Upon proteolytic removal of the secretion (pre-) signal, activation of the proenzyme (zymogen) is required for conversion to an active (mature) enzyme. H, D, and S represent the catalytic , aspartic acid and serine residues located in the . In this schematic representation of KLK gene structure, boxes indicate exons and lines indicate intervening introns. Author's personal copy

24 G. Pampalakis, G. Sotiropoulou / Biochimica et Biophysica Acta 1776 (2007) 22–31 of the extracellular matrix, thus, they likely play significant and prostatic fluid, KLKs are inactivated by allosteric reversible roles in tumor metastasis and invasion, and may promote tumor binding of Zn2+, as was experimentally demonstrated for: angiogenesis. KLK2, [25]; KLK3, [23]; KLK4, [26]; KLK5, [22]; KLK8, [27]; KLK12, [28]; KLK14, [29]. After ejaculation, KLKs are 2. A tissue kallikrein cascade regulates semen liquefaction reactivated due to redistribution of Zn2+ to seminogelins. Seminogelins bind Zn2+ through histidine residues at a stoi- Semenogelin I (SgI) and Semenogelin II (SgII) are secreted chiometry of at least 10 mol Zn2+/mol protein [30].Redistribution by seminal vesicles and represent major proteins in human of Zn2+ initiates a proteolytic cascade that leads to the activation semen. After ejaculation SgI, SgII and fibronectin aggregate to of multiple KLKs, mainly mediated by autoactivation of KLK5 form a gelatinous mass that is liquefied within 5 to 20 min, [31], and semen liquefaction. resulting in release of trapped spermatozoa [18–20]. One It is well documented that KLK2 can activate proKLK3 aggregation mechanism involves the formation of disulfide [32–34] in a process that resembles auto-activation of KLK2 bonds [21]. The process of liquefaction is mainly performed by (removal of 7 amino acids) [35]. Recently, it was demonstrated the action of prostate-specific antigen/kallikrein-related pepti- that KLK4 [36], KLK15 [37] and KLK5 [22] are also able to dase 3 (PSA/KLK3). A highly regulated proteolytic cascade, activate proKLK3. Furthermore, KLK14 is expressed in the initiated by ejaculation is responsible for the activation of prostate gland and secreted in semen. It was shown that proKLK3 [22,23]. At ejaculation, the sperm-rich epididymal proKLK14 is activated by KLK5 [31], and mature KLK14 is fluid is mixed with prostatic fluid, containing KLKs 2, 3, 4, 5, 8, able to activate proKLK5 [31]. In addition, KLK5 can efficiently 11, 12, 14, 15 [expression profile is reviewed in [8]] and is degrade SgI, SgII and fibronectin [31,38], thus, promoting accompanied by secretions of seminal vesicles (i.e. SgI, SgII, semen liquefaction. Similarly, KLK14 cleaves fibrinogen, and it fibronectin) that constitute the semen. An important feature of is likely implicated in digestion of the seminal clot [29]. prostate and prostatic fluid is its high concentration of zinc ions On the other hand, semen liquefaction is regulated by autolytic (Zn2+) [24]. Under physiological conditions, within the prostate internal cleavage of the participant proteases that results in

Fig. 2. Semen liquefaction cascade. The cascade involves several KLKs as well as plasmin [36,43,44] and TGF beta-1 [49]. In prostatic fluid, KLKs are present as latent molecules through Zn2+ binding. At ejaculation, mixing of prostatic fluid with epididymal and seminal vesicle fluids, results in Zn2+ redistribution and activation of KLKs [30]. inKLK indicates an inactive KLK. FN, fibronectin; proPlg, proplasminogen; uPA, -type . Author's personal copy

G. Pampalakis, G. Sotiropoulou / Biochimica et Biophysica Acta 1776 (2007) 22–31 25 complete inhibition of their enzymatic activities. Recently, respectively [57,58] as a result of down-regulation of the zinc KLK5 was shown to be responsible for the internal cleavage and transporter protein (hZIP1) [59,60] that is considered as a inactivation of KLK3 in vitro. The resulting proteolytic critical early event in the development of prostate cancer [59]. fragments were analyzed by N-terminal sequencing and shown Additionally, down-regulation of hZIP2, another zinc transpor- to be identical with natural peptides found in semen [22].No ter protein has been associated with prostate cancer develop- other protease is known to inactivate KLK3 by proteolytic ment [60]. High concentrations of Zn2+ present in the prostate processing and production of these internal fragments (starting at inhibit the enzymatic activity of multiple kallikreins (KLK2, KLK3 amino acid residues: R85, K182). In addition, KLK5 KLK3, KLK4, KLK5, KLK8, KLK14), as mentioned. inactivates KLK2 [22],whileKLK14wasshowntobe In prostate cancer, decrease in Zn2+ concentration leads to inactivated by autolytic processing [29]. KLK11 is another increased tissue kallikrein activity, in a way that is similar to kallikrein-related peptidase expressed in prostate and seminal the seminal cascade described above. The important role of plasma at relatively high concentrations [39]. It has been Zn2+ in prostate cancer was demonstrated in vitro by showing demonstrated that mature KLK12 activates proKLK11. KLK12 that Zn2+ can inhibit the invasive potential of KLK3- is auto-activated and subsequently auto-inactivated [28].A expressing LNCaP prostate cancer cells assessed by Matrigel putative physiological inactivator of mature KLK11 is plasmin assay [61]. Over-activation of KLKs leads to degradation of [40], which is present in semen [41]. The resulting KLK11- multiple components of the extracellular matrix (ECM) by derived proteolytic fragment is partially inactive. Approxi- specific KLKs and promotes tumor growth, metastasis and mately, 60% of KLK11 is present in a cleaved form, in which, the invasion. More specifically, KLK3 [62,63], KLK5 [38], KLK8 two resulting peptides are held together by disulfide bonds [40]. [64], and KLK14 [29] can efficiently cleave ECM compo- The biological role of KLK11, KLK12 and KLK8 [42] in semen nents, such as laminin, gelatin, fibrinogen, entactin, nidogen, has not been established yet. several types of collagen and fibronectin, as demonstrated In semen, a crosstalk between the plasmin and kallikrein experimentally [2]. Detailed analysis of substrate specificity pathways was reported [36,43,44]. Both KLK4 and KLK2 can by phage display approaches revealed that KLK2 cleaves release active plasmin, which in turn can liquefy the seminal clot ADAMTS8, cadherin-related tumor suppressor homologue and control the activity of other KLKs by proteolytic degrada- precursor and collagen IX α-chain, indicating that KLK2 is tion. Plasmin inhibitors were shown to display an inhibitory directly involved in cancer progression [65]. KLK2 is a known effect on semen liquefaction [45]. Another interesting physio- activator of proKLK3 [32–34]. On the other hand, KLK3 logical pathway that is connected to human tissue kallikreins activates proMMP2, which is a major ECM degradative leads to the activation of TGF beta-1 present in semen, where enzyme [63]. Furthermore, KLK2 was shown to activate the TGF beta-1 is found as a latent complex at a very high zymogen of single-chain form of urokinase-type plasminogen concentration in semen as compared to other biological fluids activator (uPA) [44] in vitro and to inactivate plasminogen [46–48]. Activation of TGF beta-1 in vitro proceeds in acidic activator inhibitor-1 (PAI-1), the primary inhibitor of uPA, pH. The acidic environment of the vagina may contribute to the which suggests another indirect way to activate uPA-mediated activation of TGF beta-1, which may, in turn, proceed through proteolysis [66]. More specifically, KLK2 inactivates 6–7 mol KLK3/PSA [49] or plasmin [50]. The physiological role of TGF of PAI for every mole of KLK2:PAI-1 complex formed [66]. beta-1 is to interact with epithelial cells in the cervix and uterus, Then, uPA binds to its cell surface receptor (uPAR) and in order to activate cytokine synthesis to induce cellular and converts plasminogen to plasmin, leading to efficient ECM molecular changes resembling a classical inflammatory cascade. degradation. The cytokines released by seminal activation have embryo- Tissue kallikreins can additionally facilitate the progression trophic properties [51]. The described cascade that leads to of prostate cancer by proteolytic cleavage of insulin-like growth semen liquefaction is schematically summarized in Fig. 2. factor binding proteins (IGFBPs). KLK2 cleaves IGFBP2, 3, 4, Additionally, semen liquefaction is regulated by inhibitory and 5 [67], KLK3 cleaves IGFBP3, 4 [67,68]. KLK5 was serpins. The -inhibitor (PCI) is considered to be the shown to cleave IGFBP1, 2, 3, 4, and 5 [22]. KLK14 cleaves physiological inhibitor of KLK3/PSA in semen [52]. Com- IGFBP2 and 3 [29]. Cleavage of IGFBPs leads to an increased plexes of KLK3/PSA with PCI in ejaculates are responsible for availability of insulin-like growth factors (IGFs) that bind and the inactivation of up to 5% of KLK3/PSA activity [52]. activate IGF receptor type 1 and this way modulate cell Formation of tertiary complexes of PCI with SgI and SgII is survival, mitogenesis, and differentiation. The interaction of another way of control of the KLK3-catalyzed degradation of KLKs with IGFBPs in vivo is considered to occur in the tumor seminogelins [53,54]. In addition, a complex of KLK2 with PCI microenvironment in the prostate. Recently, it was shown that was detected in semen [55]. proteinase activated receptors (PARs) are activated by KLK5, KLK6 and KLK14 [69]. Activation of PARs by KLKs may 3. Involvement of a tissue kallikrein cascade in prostate contribute to prostate cancer progression. cancer As mentioned previously, KLK3 can activate TGF beta-1, however, this reaction requires acidic pH [49]. Prostate cancer The prostate tissue is known to accumulate high cellular cells express high levels of TGF beta-1, which seems to enhance levels of Zn2+ [56]. In prostate cancer, the concentration of Zn2+ prostate cancer growth and metastasis, by stimulating angio- falls 10 to 20 fold in prostatic tissue and prostatic fluid, genesis and by inhibiting immune responses directed against Author's personal copy

26 G. Pampalakis, G. Sotiropoulou / Biochimica et Biophysica Acta 1776 (2007) 22–31 tumor cells. Although TGF beta-1 exerts anti-proliferative and and/or amplification, co-regulator alterations, and most often, pro-apoptotic effects, prostate cancer cells acquire resistance from androgen independent activation of AR as a result of cross- through their down-regulation of TGF beta-1 receptors [70]. talk between multiple signal transduction pathways [73,74]. In addition, kallikrein cascades probably regulate osteoblas- Several studies have shown that expression of KLK3 is tic metastasis of prostate cancer cells that occurs in close to 90% regulated by androgens, however, in advanced stages of prostate of prostate cancer cases and is associated with drug resistance cancer, increased levels of acetylated histone 3 (H3) at the and increased mortality. Recently, it was shown that knockout of KLK3 promoter lead to androgen-independent KLK3 expres- KLK3/PSA expression by RNA interference resulted in reduced sion. The AR is indirectly involved in regulation of KLK3 adhesion of prostate cancer cells to bone marrow epithelial cells expression in androgen-independent prostate cancer, since [71]. Furthermore, KLK3/PSA can induce proliferation, activa- knockdown of AR by RNA interference results in chromatin tion and detachment of cultured osteoblast in vitro [49,72] and remodeling and KLK3 silencing [75,76]. Similarly, H3 in vivo [72]. Fig. 3 summarizes the kallikrein cascade pathway hyperacetylation results in up-regulation of KLK2 in andro- involved in prostate cancer progression and metastasis, as gen-independent prostate tumors. Taken together, these results currently established. suggest that functional selection of efficient expression of Finally, is should be mentioned that kallikrein cascades are kallikrein genes may aid tumor growth in the absence of additionally regulated at the level of transcription. It is well androgens [76]. established that expression of most kallikrein genes is regulated by androgens and other steroid hormones [8]. 4. The role of tissue kallikrein cascade in skin Androgen receptor (AR) signaling, in particular, is critical at desquamation all stages of prostate cancer development. Primary prostate cancer is most often dependent on androgens, while androgen The skin cascade that leads to desquamation is regulated independency is associated with progression to metastatic by SPINK5 (serine protease inhibitor Kazal-type 5). Muta- disease and poor survival due to evolution of resistance to tions in SPINK5 cause the Netherton syndrome [77], a multi- androgen ablation therapies [73]. Androgen-independent system ichthyosiform syndrome characterized by ichthyosis, growth of prostate cancer may result from AR gene mutations erythroderma, hair shaft defects and atopic features [78].

Fig. 3. Prostate cancer progression cascade. In prostate cancer, concentration of Zn2+ falls dramatically to levels where KLKs become active in the prostate in a manner analogous to the semen liquefaction cascade shown in Fig. 2. KLK3 mediates binding of metastatic prostate cancer cells to bone marrow endothelial cells probably mediated by an as yet unidentified receptor indicated with a ?. ECM, extracellular matrix; IGFBP, insulin-like growth factor binding protein. Author's personal copy

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Fig. 4. Skin desquamation cascade. Arrows depicted as double lines denote pathways inhibited by SPINK5-derived peptides. KLKs are involved in the degradation of various skin proteins [80,81] as well as in the antimicrobial protection of skin [92]. SPCs, -like ; CPs, carboxypeptidases; CDSN, corneodesmosin; DSG1, desmoglein 1; DSC1 desmocollin 1.

Involvement of SPINK5 is supported by the phenotype of a keratosis phenotype was observed [87], indicating an important SPINK5(−/−) mouse that resembles the Netherton syndrome role of KLK8 in skin physiology. KLK14 is inhibited by [79]. SPINK5(−/−) mouse is characterized by enzymatic LEKTI (Lympho-epithelial Kazal-type-related inhibitor), an hyperactivity in the stratum corneum due to the enzymatic inhibitory peptide derived from SPINK5 [88], while SPINK5- activity of KLK5 and KLK7 [79]. In addition, mice with a derived peptides also inhibit the enzymatic activity of KLK5 premature termination codon in SPINK5 (R820X) develop [88–90], KLK7 [90] and KLK6 [89]. KLK6 likely plays an severe Netherton syndrome, resulting in death a few hours important role in the differentiation process of keratinocytes after birth [80]. These mice were characterized by enhanced [91] and in psoriasis [[92], Pasmatzi et al. 2007, personal proteolytic processing of profilaggrin [80]. SPINK5 is a communication]. In addition, BSSP (Brain and Skin Serine secretory serpin [81]. Proteolytic processing of SPINK5 is Protease), the mouse orthologue of KLK6 [93] is up-regulated required for the generation of bioactive peptide inhibitors in the mouse skin carcinogenesis model [94]. Therefore, it is [82]. Several enzymes are involved in proteolytic processing considered that KLK6 participates in the skin kallikrein of SPINK5 that results in the production of at least 14 cascade. It should be mentioned that the enzymatic activity of polypeptides, each possessing one or a few serine protease KLK6 is regulated by an autocatalytic mechanism of initial inhibitor domains [83]. autolytic activation and subsequent auto-inactivation by inter- As mentioned, proKLK5 is autoactivated [31], subsequently, nal cleavage at R80 [95]. active KLK5 activates proKLK7 and proKLK14 [31]. KLK14 Interestingly, kallikrein-related peptidases were recently further increases the enzymatic activity of KLK5 by activating shown to play significant roles in the antimicrobial protection proKLK5 [31]. KLK5 was shown to cleave corneodesmosin, of skin. More specifically, KLK5 and KLK7 were shown to desmoglein 1, and desmocollin 1 [84,85], while KLK7 can process the pro-form of cathelicidin (hCAP18) [96].In cleave corneodesmosin and desmocollin 1 [84,85]. KLK14 is accordance, it was found that, epidermal extracts of SPINK5 responsible for 50% of trypsin-like activity of the plantar stratum deficient mice display high antimicrobial activity [96]. Fig. 4 corneum [86]. Recently, KLK8 was reported to participate in summarizes the kallikrein cascade involved in skin desquama- the skin desquamation process. In KLK8(−/−) mice, a hyper- tion, as currently established. Author's personal copy

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5. Tissue kallikreins are involved in psoriasis and skin Furthermore, KLK1 is able to cleave proinsulin, low density cancer lipoprotein (LDL), the precursor of atrial natriuretic factor, prorenin, vasoactive intestinal peptide, procollagenase, and A number of common skin diseases such as, psoriasis angiotensinogen [reviewed in [106]], although release of kinin is vulgaris, seborrheic keratosis, lichen planus, and squamous considered the primary function of KLK1. The vasolidator, cell carcinoma display high levels of KLK8 as determined by natiuretic, and diuretic effects of KLK1 are mediated by the Northern blot and in situ hybridization analysis [97].In release of eicosanoids, NO, and endothelium-derived hyperpo- psoriasis, KLK7 is also up-regulated compared to normal skin, larizing factor [107]. Importantly, KLK1 may represent the in particular, in psoriatic lesions as compared to the non- physiological regulator of calcium metabolism as indicated by lesional psoriatic skin. Both active as well as proKLK7 are the phenotype of KLK1 knockout mouse [108]. detected in psoriatic lesions where conversion of proKLK7 to Regulation of KLK1 activity by SPINK5 is considered to KLK7 occurs, and KLK7 is likely the epidermal enzyme that occur in the central nervous system. In the pituitary, KLKs 5–8 activates interleukin 1 beta (IL-1b) [98], while it degrades and 10–14 are co-expressed with SPINK5. It was further shown beta-glucocerebrosidase and acidic sphingomyelinase, two that KLK 4–6, 8, 13 and 14 are able to cleave and process the major lipid processing enzymes responsible for the basal human growth hormone (hGH). Therefore, a complex KLK permeability barrier function of the stratum corneum [99].Itis cascade is expected to exist in the human pituitary that is worth noting that, although the putative role(s) of specific responsible for the proteolytic processing of hGH [88]. KLKs in skin cancer have not been examined, tissue In addition, the co-existence of KLK3 and KLK2 in various microarray profiling of gene expression revealed KLK6 as biological fluids indicates the operation of KLK cascades. one of the few most highly up-regulated genes upon induction Nipple aspirate fluid [109,110], breast milk [111] and amniotic of differentiation of squamous cell carcinoma by the vitamin fluid [25] are examples of biological fluids known to contain D3 analog EB1089 [91]. On a similar note, both KLK6 and both KLK2 and KLK3, while nipple aspirate fluid also contains KLK10 were among the genes that were significantly up- KLK6 and KLK10 [109]. regulated in colon cancer cells induced to differentiate by EB1089 [100]. Further, vitamin D3 regulates the expression of 7. Conclusions KLK5, 6, 8, 10 and 13 in normal keratinocytes and constitutes an essential part of their vitamin D3-induced differentiation This review summarizes very recent data that show the network [101]. These results implicate KLK6 and KLK10 in operation of KLK enzymatic cascades in various tissues. skin carcinogenesis given that impairment of cellular KLKs are all secreted serine proteases, their enzymatic activity differentiation is an essential part of tumor development. requires the proteolytic removal of a propeptide sequence, and Therefore, complex kallikrein cascades that remain to be many KLKs display parallel expression in certain tissues identified are involved in the differentiation process in skin. where they may act on diverse protein substrates. This is Interestingly, immunohistochemical analysis revealed expres- consistent with the presence of a KLK cascade. Sequential sion of KLK3/PSA in cutaneous and metastatic malignant activation of human KLK zymogens in a way that resembles melanomas [102]. Although causal role of KLK3/PSA in the activation of the blood coagulation cascade, food digestion melanoma has not been established, another study suggested cascade, etc. may underlie the regulation of multiple that the expression of KLK3/PSA in cutaneous metastases physiological processes, while its aberrant function could acts as a marker for the prostatic origin of metastasis [103]. promote certain pathological conditions in the prostate tissue Given that plasmin causes increased motility of melanoma and in skin. An overview on our present understanding of cells [104], kallikrein cascades that lead to activation of putative crosstalks between KLK proteolytic cascade pathways plasmin, as demonstrated for KLK2 and KLK4 [36,43,44], and other protease-mediated pathways and their modes of are likely responsible for migration and metastasis of melanoma regulation was presented. cells and/or other forms of skin cancer. 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