Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis

Abstract

To define a functional role for the endosomal/lysosomal cysteine protease cathepsin L (Ctsl) during squamous carcinogenesis, we generated mice harboring a constitutive Ctsl deficiency in addition to epithelial expression of the human papillomavirus type 16 oncogenes (human cytokeratin 14 (K14)–HPV16).We found enhanced tumor progression and metastasis in the absence of Ctsl. As tumor progression in K14–HPV16 mice is dependent on inflammation and angiogenesis, we examined immune cell infiltration and vascularization without finding any effect of the Ctsl genotype. In contrast, keratinocyte-specific transgenic expression of cathepsin V, the human orthologue of mouse Ctsl, in otherwise Ctsl-deficient K14–HPV16 mice restored the phenotype observed in the control HPV16 skin. To better understand this phenotype at the molecular level, we measured several oncogenic signal transduction pathways in primary keratinocytes on stimulation with keratinocyte-conditioned cell culture medium. We found increased activation of protein kinase B/Akt and mitogen-activated protein kinase pathways in protease-deficient cells, especially if treated with media conditioned by Ctsl-deficient keratinocytes. Similarly, the level of active GTP-Ras was increased in Ctsl-deficient epidermis. We conclude that Ctsl is critical for the termination of growth factor signaling in the endosomal/lysosomal compartment of keratinocytes and, therefore, functions as an anti-tumor protease.

Human Cathepsin V Protease Participates in Production of Enkephalin and NPY Neuropeptide Neurotransmitters

“…Expression of cathepsin V in the cathepsin L knock-out mouse rescues defects in T cell function (37) and keratinocyte proliferation (38,39). These findings indicate that human cathepsin V and mouse cathepsin L share similar functions, consistent with their high homology (74.6% protein sequence identity for cathepsin V and cathepsin L) (31).…”

Cysteine Cathepsins S and L Modulate Anti-angiogenic Activities of Human Endostatin

“…More than 30 proteases, including cysteine cathepsins, have been catalogued with beneficial tumor-suppressive roles in opposition to the currently established rule that their up-regulation is synonymous with tumor progression and poor clinical prognosis (41). Contrary to other previous studies, cathepsin L KO mice displayed early onset aggressive tumors and an hyperproliferation of keratinocytes in a skin carcinogenesis model, proving that cathepsin L may have a protective role in cancer in association with its critical role for the termination of growth factor signaling (42,43). These statements emphasize that proteases may have dual roles and exert for instance opposing proangiogenic and angiostatic effects.…”

Cathepsin C is a tissue-specific regulator of squamous carcinogenesis

“…Tissue specificity is a significant determinant of expression and activity for multiple classes of proteolytic enzymes, an issue that befuddled clinical trials of matrix metalloproteinase (MMP) inhibitors (Coussens et al 2002). For example, whereas CtsL is a regulator of proteolytic networks in the skin (Tholen et al 2013) and is protective against squamous cell (Dennemarker et al 2010;Benavides et al 2012) and two-stage chemical (Benavides et al 2012) carcinogenesis, CtsL is critical for pancreatic islet tumor growth (Gocheva et al 2006). Based on this, it is now clear that understanding not only temporal dynamics of protease function but also organ specificity in which individual proteases exert functional capacity is of paramount importance for clinical translation.…”

“…Subsequent studies using RIP-Tag2 mice genetically deficient for individual Cts proteases (e.g., CtsB, CtsL, and CtsS genes) revealed their individual roles in regulating tumor progression (Gocheva et al 2006). In particular, CtsB and CtsS exert protumorigenic activities during pancreatic islet (Gocheva et al 2010;Gopinathan et al 2012), mammary (Vasiljeva et al 2006), and intestinal carcinogenesis (Gounaris et al 2008); CtsL, on the other hand, limits intestinal (Boudreau et al 2007), squamous cell (Dennemarker et al 2010), and two-stage chemical (Benavides et al 2012) carcinogenesis but is protumorigenic in pancreatic islet tumors (Gocheva et al 2006). Thus, individual Cts proteases possess distinct roles during tumor development that are likely guided by characteristics of the tissue and organ microenvironment.…”