Cathepsin L targeting in cancer treatment

Abstract

Proteolytic enzymes may serve as promising targets for novel therapeutic treatment strategies seeking to impede cancer progression and metastasis. One such enzyme is cathepsin L (CTSL), a lysosomal cysteine protease. CTSL upregulation, a common occurrence in a variety of human cancers, has been widely correlated with metastatic aggressiveness and poor patient prognosis. In addition, CTSL has been implicated to contribute to cancer-associated osteolysis, a debilitating morbidity affecting both life expectancy and the quality of life. In this review, we highlight the mechanisms by which CTSL contributes to tumor progression and dissemination and discuss the therapeutic utility of CTSL intervention strategies aimed at impeding metastatic progression and bone resorption.

Keywords: Bone resorption; Cancer; Cathepsin L; Metastasis; Protease targeting.

Figure 1. Distinct roles of secreted and nuclear CTSL

Secreted CTSL aids metastatic dissemination of tumor cells by degrading cell adhesion molecules and extracellular matrix proteins as well as activating other latent proteases. Nuclear CTSL activates the transcription of epithelial to mesenchymal transition genes and also confers therapeutic resistance.

Figure 2. CTSL deficiency impairs invasiveness of pancreatic islet tumors in RIP-1 Tag-2 mice

Tumors in RT2 mice can be classified into three different grades A. Encapsulated tumor (Tum), B. microinvasive tumors (IC1) and C. invasive carcinomas (IC2). D. Representative image for the predominant grade in CTSL knockout mice is shown. E. Distribution of tumor types in control and CTSL knockout tumors. Immunofluorescence images indicating increased E-Cadherin levels in CTSL knockout (H and I) compared to control (F and G) tumors (Red, E-cadherin; blue, DAPI). Modified with permission from Gocheva et al (2006). Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes & Development, 20:543-556, under a Creative Commons License (Attribution-NonCommercial 4.0 International License).

Figure 3. Tumor microenvironmental conditions such as hypoxia and acidosis enhance CTSL secretion and tumor cell invasiveness

A. and C, CTSL secretion by prostate cancer PC-3ML cells upon exposure to hypoxic or acidic conditions. B. and D, PC-3ML invasiveness in response to such conditions. Modified with permission from Sudhan et al (2013). Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells. Clinical & Experimental Metastasis, 30:891-902.

Figure 4. Effect of CTSL inhibition on metastasis

A. Effect of CTSL specific inhibitor KGP94 on migratory capacity of OS-156 osteosarcoma cells. B. Anti-invasive effect of KGP94 across various tumor cell types; osteosarcoma cells (OS-156), androgen dependent prostate cancer cells (LNCaP), androgen resistant bone metastatic prostate cancer cells (C42B), and highly lung metastatic breast cancer cells (LM2-4175). C. Effect of CTSLi KGP94 treatment on lung metastases forming capacity of SCCVII squamous carcinoma cells, mice (N>9) treated with daily 20 mg/kg doses of the CTSL inhibitor KGP94. Line, median; bars 25^th and 75^th percentiles. D. Representative images of lungs from C.