Markers cathepsins

R3. Rochefort, H., Cathepsin D in breast cancer A tissue marker associated with metastasis. Eur. 

In aminoglycoside-treated animals, the cells can be led to canonical apop-totic death through activation of caspases. Caspase-9 forms an apoptosome complex with cytochrome c and APAF-1 and leads to apoptosis through activation of caspase-3. Aminoglycosides activate caspases in auditory structures conversely, inhibition of caspase activity successfully blocks neomycin-induced vestibulotoxicity. In contrast, apoptotic markers were essentially absent in a mouse model of chronic kanamycin ototoxicity where death of auditory sensory cells ensued via cathepsins. The activation of cathepsin D was accompanied by the nuclear translocation of endonuclease G, necrotic cleavage of PARP, and activation of p,-calpain, all facets of necrotic cell death. 

Cat B is an abundant and ubiquitously expressed cysteine peptidase of the papain family and makes up a major fraction of lysosomal enzymes that is capable of degrading components of the extracellular matrix in various diseases [30-32]. Cat B is also a prognostic marker for several types of cancer [33], and increased expression and secretion of cat B has been shown to be involved in the migration and invasion of various tumours [34—36], The precise role of cat B in solid tumours is not fully understood, but it has been proposed to participate, along with other cysteine cathepsins, in metastasis, angiogenesis, and tumour progression [37], Indeed, cat B inhibitors reduce both tumour cell motility and invasiveness in vitro [38], Recently, metal complexes based on rhenium, gold and palladium were shown to be effective inhibitors of cat B [39-44],... 

Osteoclasts are multinucleated cells found on the endosteal surface of bone, in Haversian systems and periosteal surfaces. PTH activates osteoclasts (indirectly via osteoblasts that possess PTH receptors). Calcitonin is a potent inhibitor of osteoclast activity. Local cytokine factors, including interleukin-1 (IL-1), tumour-necrosis factor (TNF), TGF- 0 and interferon-y (INF-y), are important regulators. Osteoclast resorption of bone releases collagen peptides, pyridinoline cross-links and calcium from the bone matrix, through the action of lysosomal enzymes (collagenases and cathepsins). The collagen breakdown products in serum and urine (e.g. hydroxyproline) can be used as biochemical markers. 

Figure 9-14. Frequency distribution of various marker enzymes for lysosomes (acid phosphatase, cathepsin, etc.), peroxisomes (urate oxidase) and mitochondria (cytochrome oxidase). Mitochondrial fraction from rat liver centrifuged in a linear gradient of 0.25 to 0.5M sucrose. [From H. Beaufay et al., Biochem. /., 73 628 (1959).]...

INTERNET LINK Cathepsin D as a Marker for Breast Cancer... 

Figure 2. The polypeptide chains of human cathepsin D. The samples run in electrophoresis in the presence of sodium dodecyl sulphate were (a) molecular weight markers, ovalbumin (43,000), carbonic anhydrase (29,000) and chicken lysozyme (14,300) (b) 3-form of human cathepsin D treated with mer-captoethanol (c) 3-form of human cathepsin D treated with iodoacetate. The direction of migration was downward, in an electrophoretic system similar to that of Alvares and Seikevitz (24). Doublets at about 30,000 and 14,000 molecular weight indicate that there are two bonds close together in the molecule susceptible to cleavage. No uncleaved molecules were detected in the region of 43,000 molecular weight.

Also in support of the location of cathepsin M on the outer lysosomal surface were results obtained with a monoclonal antibody prepared against the rabbit liver enzyme. This antibody, but not another monoclonal antibody specific for platelet surface markers, could be shown to bind to the intact lysosomes. In addition, rabbit liver lysosomes could be shown to bind to monoclonal anti-cathepsin M coupled to Sepharose 4B, but not to Sepharose 4B alone or to a coupled monoclonal antibody directed against surface glycoprotein of human platelets (Table II). 

Lysosomes contain several proteinases which have been historically called cathepsins. The proteinases are glycoproteins, have acid pH optima, and are possibly attached to the inner side of the lysosomal membrane. Lysosomal involvement in the breakdown of intracellular proteins has been inferred from electron microscopic data showing regions of membrane engulfing cell constituents, as well as whole and partially degraded mitochondria enclosed in organelles which are rich in lysosomal marker enzymes (Ericsson, 1969 Barrett, 1969). 

---