Cathepsin L in metastatic bone disease: therapeutic implications

Abstract

Cathepsin L is a lysosomal cysteine proteinase primarily devoted to the metabolic turnover of intracellular proteins. However, accumulating evidence suggests that this endopeptidase might also be implicated in the regulation of other important biological functions, including bone resorption in normal and pathological conditions. These findings support the concept that cathepsin L, in concert with other proteolytic enzymes involved in bone remodeling processes, could contribute to facilitate bone metastasis formation. In support of this hypothesis, recent studies indicate that cathepsin L can foster this process by triggering multiple mechanisms which, in part, differ from those of the major cysteine proteinase of osteoclasts, namely cathepsin K. Therefore, cathepsin L can be regarded as an additional target in the treatment of patients with metastatic bone disease. This review discusses the clinical and therapeutic implications related to these findings.

The heparanase system and tumor metastasis: is heparanase the seed and soil?

“…As noted above, cathepsin L expression is upregulated in many human tumors. Notably, cathepsin L expression was predominantly enhanced in primary bone tumors such as osteosarcoma, chondrosarcoma, and multiple myeloma, in tumors which preferentially metastasize to bone (i.e., breast and prostate cancer), and in bone metastases [76]. The hypothesis that cathepsin L contributes to bone metastasis is supported by experimental observations signifying that administration of selective cathepsin L antagonists prevents or inhibits cancer-related bone resorption in mice [32,76].…”

“…These results indicate that in spite of the close resemblance between cathepsin family members, cathepsin L plays an important, non redundant role in the process of tumor development and invasion, thus justifying the development of cathepsin L inhibitors. A step toward implementing cathepsin L inhibitors as anti-cancer therapeutics was demonstrated in metastatic bone disease [76].…”

“…Notably, cathepsin L expression was predominantly enhanced in primary bone tumors such as osteosarcoma, chondrosarcoma, and multiple myeloma, in tumors which preferentially metastasize to bone (i.e., breast and prostate cancer), and in bone metastases [76]. The hypothesis that cathepsin L contributes to bone metastasis is supported by experimental observations signifying that administration of selective cathepsin L antagonists prevents or inhibits cancer-related bone resorption in mice [32,76]. Utilizing computer modeling, Katunuma reported the development of cathepsin L inhibitors directed to block the substrate binding pocket and named the series cathepsin L inhibitor Katunuma (CLIK) [77].…”

Purinergic signalling and cancer

“…Expression of cathepsin L, a cysteine protease associated with cancer metastasis, which activates heparanase, is predominately enhanced in primary bone tumours, such as osteosarcoma, chrondrosarcoma and multiple myeloma, and tumours which preferentially metastasise to bone (i.e. breast and prostate cancer) and in bone metastases [326]. ATP, ADP and adenosine were most effective in stimulating secretion of active heparanase by tumour cells [327].…”

Vitamin D in cancer chemoprevention

“…Additionally, more recent studies show that 1,25(OH) 2 D 3 treatment can protect BPH-1 human prostate epithelial cells from carcinogen-induced genotoxic stress via VDR-mediated transcriptional upregulation of DNA repair genes, ATM and RAD50, thereby facilitating DNA double-strand break repair (Ting et al, 2012). Interestingly, on one hand, recent findings stress that in BRCA1-deficient breast cancer cells, Vit D prevents the degradation of the DNA repair protein 53BP1 mediated by cysteine proteinases Cathepsin L (Gonzalo, 2014), a lysosomal endopeptidase which is involved in tumor cell proliferation, invasion, and metastasis (Gonzalo, 2014;Lankelma et al, 2010;Leto et al, 2010). On the other hand, recent observations report that the gene encoding the BRCA1 protein is a critical downstream target of Vit D. Consistent with these data Campbell et al (2000) show that treatment of MCF-7 cells with calcitriol results in a near 6-fold increase in BRCA1 protein and that VDR expression is directly correlated with induction of BRCA1.…”