multifunctional enzymes in cancer

Abstract

Cysteine cathepsins are highly upregulated in a wide variety of cancers by mechanisms ranging from gene amplification to post-transcriptional modification. Their localization within intracellular lysosomes often changes during neoplastic progression, resulting in secretion of both inactive and active forms and association with binding partners on the tumour cell surface. Secreted, cell-surface and intracellular cysteine cathepsins function in proteolytic pathways that increase neoplastic progression. Direct proof for causal roles in tumour growth, migration, invasion, angiogenesis and metastasis has been shown by downregulating or ablating the expression of individual cysteine cathepsins in tumour cells and in transgenic mouse models of human cancer.

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

“…Cathepsins were initially characterized as specific lysosomal markers, and the release of mature forms in the extracellular compartment was observed from epithelial cells (Rodriguez et al, 1997) as well as immune cells (Lopez-Castejon et al, 2010) and proposed to be mainly due to lysosomal exocytosis. These proteases are often upregulated in various human cancers including breast cancer and are implicated in numerous tumourigenic processes, such as invasion and metastasis (Mohamed and Sloane, 2006). They are known to be extracellularly active, even if the events leading to their extracellular secretion or activation are not well understood.…”

“…To confirm the specificity of cathepsin activity in supernatants, we pre-incubated samples coming from ATP-stimulated cells with the cathepsin inhibitor E64 and in that case fluorescence release was almost inexistent (Figure 6d). Among all members of cysteine cathepsins, the cathepsin B has been involved in the progression of different cancers (Mohamed and Sloane, 2006). Cathepsin B was immunodetected under its inactive proform (46 kDa) and two active forms, the single-(31 kDa) and double-chain (24-25 kDa) forms (Figure 6e).…”

“…Their proteolytical disruption, by extracellular proteases, allows tumour cells to progress to malignancy and metastasis. In the last decade, studies mainly focused on the involvement of matrix metalloproteinases in the neoplastic progression (Egeblad and Werb, 2002), but recently, it appeared that cysteine cathepsins are highly upregulated in a wide variety of cancers, including breast cancer (Mohamed and Sloane, 2006). Indeed elevated cathepsin B expression correlates with poor prognosis in breast cancer as in other cancers (Jedeszko and Sloane, 2004) and its activity has been shown to enhance breast cancer cells invasiveness in vitro (Gillet et al, 2009).…”

NaV1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae

“…The development of metastases consists of a complex series of events. One key step is the acquisition by cancer cells of an invasive potency, mainly relying on the capacity to degrade basement membranes and extracellular matrices (Gupta and Massague, 2006) by various proteases such as matrix metalloproteinases (Egeblad and Werb, 2002) or cysteine cathepsines (Mohamed and Sloane, 2006). We and others have shown that voltage-gated sodium channels (Na V ) are abnormally expressed in cancer cells of epithelial origin and associated with cancer progression (Laniado et al, 1997;Roger et al, 2003Roger et al, , 2006Roger et al, , 2007Fraser et al, 2005;Diaz et al, 2007).…”

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

“…The cathepsin family consists of cysteine, aspartate, and serine lysosomal proteases that play an important role in many physiological and pathological processes (Turk et al, 2000;Sloane et al, 2005;Mohamed and Sloane, 2006;Vasiljeva et al, 2007;Conus and Simon et al, 2008). Among these, cathepsin B is involved in the degradation of cellular proteins in lysosomes and functions as an endopeptidase at neutral pH.…”