Bone Microenvironment Modulates Expression and Activity of Cathepsin B in Prostate Cancer

Abstract

Prostate cancers metastasize to bone leading to osteolysis. Here we assessed proteolysis of DQ-collagen I (a bone matrix protein) and, for comparison, DQ-collagen IV, by living human prostate carcinoma cells in vitro. Both collagens were degraded, and this degradation was reduced by inhibitors of matrix metallo, serine, and cysteine proteases. Because secretion of the cysteine protease cathepsin B is increased in human breast fibroblasts grown on collagen I gels, we analyzed cathepsin B levels and secretion in prostate cells grown on collagen I gels. Levels and secretion were increased only in DU145 cells--cells that expressed the highest baseline levels of cathepsin B. Secretion of cathepsin B was also elevated in DU145 cells grown in vitro on human bone fragments. We further investigated the effect of the bone microenvironment on cathepsin B expression and activity in vivo in a SCID-human model of prostate bone metastasis. High levels of cathepsin B protein and activity were found in DU145, PC3, and LNCaP bone tumors, although the PC3 and LNCaP cells had exhibited low cathepsin B expression in vitro. Our results suggest that tumor-stromal interactions in the context of the bone microenvironment can modulate the expression of the cysteine protease cathepsin B.

Molecular Biology of Bone Metastasis

“…Cathepsin B is a cysteine proteases expressed by tumor cells, which is activated in an acidic microenvironment and could participate in the vicious cycle of bone metastasis (76). It is expressed at low levels in primary prostate tumors; however, bone metastatic lesions express high levels of activated cathepsin B, suggesting that protease activity is modulated by interactions between tumor cells and the bone microenvironment (77).…”

MTA1 drives malignant progression and bone metastasis in prostate cancer

“…At the same time, CTSB has been shown to play an important role in invasion and metastasis of prostate cancer (Miyake et al ., 2004). Increased CTSB expression and activity were observed in bone tissues colonized by human prostate carcinoma cells (Podgorski et al ., 2005). It was suggested that metabolically rich bone microenvironment is responsible for secretion of active CTSB from prostate cancer cells interacting with the bone (Podgorski et al ., 2005).…”

“…Increased CTSB expression and activity were observed in bone tissues colonized by human prostate carcinoma cells (Podgorski et al ., 2005). It was suggested that metabolically rich bone microenvironment is responsible for secretion of active CTSB from prostate cancer cells interacting with the bone (Podgorski et al ., 2005). Our unpublished data also show induction of CTSB expression in prostate cancer cells, when cocultured with bone cells than when cultured alone.…”

“…We showed that MTA1 ablation profoundly suppressed the growth of prostate tumors and the ability of tumor cells to colonize the bone by inhibiting their migratory and invasive properties through repression of cathepsin B (CTSB), a cysteine protease that plays a critical role in bone metastasis (Podgorski et al ., 2005; Withana et al ., 2012). …”

The Impaired Viability of Prostate Cancer Cell Lines by the Recombinant Plant Kallikrein Inhibitor

“…An increase in the expression of several proteases is verified in prostate cancer cells. This increase is especially present in serine proteases, which are involved in different events of tumor establishment, such as proliferation, adhesion, migration, angiogenesis, and apoptosis (2)(3)(4)(5)(6). The tissue serine protease kallikrein 3 (also known as prostate specific antigen) plays a relevant role in this disease; prostate cancer can be diagnosed through the quantification of prostate specific antigen levels in the serum of sick individuals (7,8).…”