CTSL

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Introduction

Proteolytic enzymes are essential in many diseases, especially in several stages of malignant tumor progression. Extracellular proteases can promote tumor growth and angiogenesis, and are also actively involved in key steps including tumor cell detachment, degradation of extracellular and interstitial matrices and basement membrane, intravasation and extravasation across the lymphatic system. Therefore, the research of these proteases and the development of intervention strategies for them have received more and more attention. Since people recognized the importance of matrix metalloproteases (MMPs) in tumor progression and metastasis, extensive MMP inhibitor development has begun. However, due to adverse side effects and/or lack of clinical benefit, many clinical trials of MMP inhibitors had to be stopped. In view of the clinical failure of these MMP inhibitors, protease targeting as a means of inhibiting tumor progression has largely fallen out of favor. Recent studies exploring other proteolytic enzyme targets have shown that if selective inhibitors of pericellular proteolysis can be developed, it may significantly impair tumor progression and metastasis, so the concept of proteolytic enzyme targeting is being revived.

This article focuses on cathepsin L (CTSL), a family member closely related to malignant progression and metastatic disease. Compared with normal tissues or benign tumors, activity assessments show that CTSL proteolytic activity is significantly higher in neoplastic tissues. The function of CTSL is also strictly regulated by the concentration of its endogenous inhibitors. Independent experimental investigations have reported that there is a significant imbalance between CTSL and endogenous inhibitors level in highly invasive breast cancer and prostate cancer cells compared with poorly invasive and weakly tumorigenic cells. This imbalance causes it to evade regulation and may participate in the unregulated activation of the proteolytic cascades.

Table 1. CTSL upregulation in human cancers (Sudhan, D.R.; Siemann, D.W. 2015)

Nuclear Cathepsin L

In addition to the secretory CTSL, many studies have also reported the existence of truncated nuclear isoform of CTSL. Nuclear CTSL lacks endoplasmic reticulum targeting signal peptides, but it does contain a putative nuclear localization signal, which may be the cause of its translocation to the nucleus. Nuclear CTSL can proteolytically process and activate the CCAAT-displacement protein/cut homeobox (CDP/Cux) transcription factor, which is closely related to the poor prognosis of the disease. CTSL processed CDP/Cux showed significantly enhanced DNA binding properties, which gave tumor cells replication and metastasis advantages. CDP/Cux can promote the proliferation of tumor cells, and also enhance the invasive characteristics of tumors by stimulating hallmark epithelial to mesenchymal transition features.

Nuclear CTSL can also promote tumor progression through other CDP/Cux independent mechanisms. Nuclear CTSL is often found to be significantly upregulated in triple negative breast cancer patients and patients with germline or somatic mutations in BRCA1 tumor suppressor gene. In fact, the increased nuclear CTSL level can be used as a predictive biomarker for this subset of breast cancer patients. BRCA1-deficient cells overcome genomic instability by overexpressing nuclear CTSL, which in turn proteolytically degrades 53BP1. Therefore, nuclear CTSL not only gives BRCA1-deficient tumor cells a survival advantage, but also improves their DNA repair capabilities and makes them resistant to radiation and genotoxic chemotherapeutics (such as PARP inhibitors, cisplatin, and mitomycin C).

Figure 1. Distinct roles of secreted and nuclear CTSL (Sudhan, D.R.; Siemann, D.W. 2015)

Cathepsin L targeting

The role of CTSL in promoting tumor progression and metastasis, as well as its contribution to cancer-associated bone resorption, has aroused great interest in the development of CTSL intervention strategies. Since the unrestrained CTSL activity stems from the imbalance between the levels of CTSL and endogenous inhibitors, some studies have attempted to eliminate the proteolytic function of CTSL by ectopic delivery or overexpression of endogenous inhibitors. It is worth noting that Gianotti et al. have done it. They verified that the anti-invasive properties of cystatin overexpression are mainly mediated by the inactivation of extracellular rather than intracellular CTSL, and further verified that the hypothesis that metastatic phenotype of tumor cells is mainly driven by secreted CTSL. In different tumor models (including osteosarcoma, glioma, myeloma, and melanoma), CTSL downregulation through RNA interference resulted in consistent inhibition of tumorigenicity and invasiveness of neoplastic cells. In addition to its anti-invasive effect, studies have reported that the inhibition of CTSL in glioblastoma also enhances the sensitivity of tumor cells to apoptotic agents.