Cathepsin B: multiple roles in cancer

Abstract

Proteases, including intracellular proteases, play roles at many different stages of malignant progression. Our focus here is cathepsin B, a lysosomal cysteine cathepsin. High levels of cathepsin B are found in a wide variety of human cancers, levels that often induce secretion and association of cathepsin B with the tumor cell membrane. In experimental models, such as transgenic models of murine pancreatic and mammary carcinomas, causal roles for cathepsin B have been demonstrated in initiation, growth/tumor cell proliferation, angiogenesis, invasion, and metastasis. Tumor growth in transgenic models is promoted by cathepsin B in tumor-associated cells, for example, tumor-associated macrophages, as well as in tumor cells. In transgenic models, the absence of cathepsin B has been associated with enhanced apoptosis, yet cathepsin B also has been shown to contribute to apoptosis. Cathepsin B is part of a proteolytic pathway identified in xenograft models of human glioma; targeting only cathepsin B in these tumors is less effective than targeting cathepsin B in combination with other proteases or protease receptors. Understanding the mechanisms responsible for increased expression of cathepsin B in tumors and association of cathepsin B with tumor cell membranes is needed to determine whether targeting cathepsin B could be of therapeutic benefit.

Keywords: Cancer; Cathepsin B; Cysteine proteases.

Figure 1

Schematic of cathepsin B protein depicting the signal sequence, propeptide, and single chain and double chain forms. Cathepsin B is compared with other cysteine cathepsins that are implicated in cancer progression. Number of amino acids for each domain is indicated in boxes: cathepsin B [31], cathepsin X/Z [144], cathepsin L [145], cathepsin V [146], cathepsin S [147].

Figure 2

Diagram of cathepsin B promoter. The promoter of cathepsin B is compared to promoters of other cysteine cathepsins that are implicated in cancer progression. These promoters are GC rich, do not have a well-defined transcription start site (lack a TATA-box), and have multiple transcription factor binding sites: cathepsin B [60, 148], cathepsin X/Z [149], cathepsin L [150], cathepsin V [151], cathepsin S [147]. Bakhshi et al. [152] and Seth et al. [153] have described two alternative cathepsin L promoters with several putative transcription factor binding sites, but here we depict three sites that Jean et al. [150] confirmed to interact with transcription factors. EBS, Ets binding site.

Figure 3

Cancers and stages of initiation and progression in which cathepsin B has been demonstrated by in vivo experimentation to play a causal role. See text for further details; names of cancers are shown italics; cartoon is adapted from [97].