Stefins and lysosomal cathepsins B, L and D in human breast carcinoma

Lah, Tamara T.; Kokalj-Kunovar, Majda; Štrukelj, Borut; Pungerčar, Jože; Barlič–Maganja, Darja; Drobnic-Kosorok, Marina; Kastelic, L.; Babnik, J.; Golouh, Rastko; Türk, Vito

doi:10.1002/ijc.2910500109

Cited by 120 publications

(72 citation statements)

References 27 publications

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“…At this point, the crucial question is whether the observed relations in cystatin C levels influenced the total intracellular proteolytic potential in the two groups. It has been shown that alterations in total inhibitory activity of cysteine proteinase inhibitors or in protein level in case of stefin A were present in malignant tissue and normal parenchyma of the breast (Lah et al, 1992 and lung (Knoch et al, 1994). In the study by Lah et al (1992), lowered cysteine proteinase inhibitor activity in breast carcinoma tissue (i.e., in the low-activity group) was associated with significantly higher increases of cathepsin B and cathepsin L activities than those measured in the high-activity group, indicating higher proteolytic potential in the former group.…”

Section: Discussionmentioning

confidence: 99%

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

et al. 2004

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To determine the role of the cysteine proteinase inhibitor cystatin C in the invasive behavior of squamous cell carcinoma of the head and neck (SCCHN), Cystatin C protein level was measured in 82 pairs of primary tumour tissue and adjacent noncancerous mucosa, using the enzyme-linked immunosorbent assay. The median level of cystatin C in tumour tissue was 1.18 times lower than that in corresponding mucosa (P ¼ 0.031). In normal mucosa samples, the cystatin C level was influenced by the site of sampling: it was lower in nonlaryngeal tissue samples (oral cavity, oro-or hypopharynx) than in laryngeal samples (P ¼ 0.004). The tumour cystatin C level correlated inversely with pN-stage (P ¼ 0.047), whereas a trend of lower cystatin C levels was observed in the group with extranodal tumour extension compared to those with no extranodal spread (P ¼ 0.069). In univariate analysis, the patients with low tumour cystatin C levels exhibited poor disease-free survival (DFS, P ¼ 0.013) and disease-specific survival (DSS, P ¼ 0.013). In multivariate analysis, the most powerful predictor of survival was pN-stage (DFS: P ¼ 0.040, HR 2.78; DSS: P ¼ 0.011, HR 4.36,), followed by the cystatin C level (DFS: P ¼ 0.043, HR 0.22; DSS: P ¼ 0.067, HR 0.25). When comparing the prognostic strength of cystatin C to that of stefin A, another cysteine proteinase inhibitor, which emerged as the most significant prognosticator for survival in our previous study analysing the same cohort of patients, stefin A proved to be significantly more reliable predictor for both DFS and DSS than cystatin C. Our results indicate that cystatin C is implicated in the invasive behavior of SCCHN, and that there are variations in regulation of proteolytic pathways under nonmalignant conditions, inherent to individual subsites inside the upper aerodigestive tract. The correlation between high cystatin C levels and improved survival concurs with the concept of the protective role of high levels of cysteine proteinase inhibitors in tissue homogenates that has been previously suggested by the survival results in breast and lung carcinoma as well as SCCHN.

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Section: Discussionmentioning

confidence: 99%

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

et al. 2004

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“…The level of cathepsin B expression is elevated in human breast and ovarian cancers (Woynarowska et al, 1989;Gabrijelcic et al, 1992;Lah et al, 1992), and in several metastatic cell lines, including ras-transformed NIH 3T3 cells and Lewis lung carcinoma cells, in which the level of expression has been correlated with the increased malignancy (Brodt et al, 1992;Chambers et al, 1992). In many malignant cell lines, the enzyme is localized to the plasma membrane and is clearly secreted in most instances (Sloane et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Cathepsin B, a Cysteine Protease Implicated in Metastatic Progression, is also Expressed During Regression of the Rat Prostate and Mammary Glands

Guenette

Mooibroek

Wong

et al. 1994

European Journal of Biochemistry

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We have developed a novel library-to-library cross-screening technology to clone unique mRNAs that are expressed during tissue regression. We have cloned a number of regression selected genes (RSG) that are expressed during the regression of the mammary gland and ventral prostate of the rat after the removal of the respective trophic hormone. In this investigation, we have characterized one of these genes, RSG-2, that is homologous to cathepsin B, a thiol protease that has been previously identified as one of the extracellular proteases which is activated in metastatic cells. The steady-state levels of RSG-2 mRNA in the normal prostate are low but detectable. In the regressing prostate, RSG-2 mRNA levels peak at 3-4 days after castration, at the time that tissue regression is maximal. The gene is induced in a similar fashion in the regressing mammary gland. Using in situ hybridization, we have established that RSG-2 mRNA is expressed in the luminal epithelial cells of the prostate and mammary gland that are known to undergo active cell death, suggesting that it may be a general marker for secretory epithelial cell death. Analysis of the distribution of the cathepsin B protein by immunofluorescence microscopy demonstrates that there is diffuse, but punctate, expression of the protein in all of the luminal epithelial cells of the normal prostate and mammary gland. However, at early times after hormone ablation in both glands, the majority of the increase in cathepsin B protein appears to result from redistribution to the basal aspect of the cells. At later time points, there appears to be increased amounts of the protein which is localized to the apoptotic bodies. These results suggest that RSG-2, or cathepsin B, is required for the local degradation of the basement membrane. which is one of the earliest morphologically recognizable events of active cell death.

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“…The ECM contains several specific protease inhibitors, including members of the family of tissue inhibitors of metalloprotease [56], plasminogen activator inhibitor [57,58]. cystatin and stefin families [59,60]. The balance between the relative level of proteases and their specific inhibitors dictates the degree of protease activity, and essentially ensures that uncontrolled proteolysis of the components of the basement membrane does not occur.…”

Section: The Integrinsmentioning

confidence: 99%

Apoptosis, tumour invasion and prostate cancer

Tenniswood

1997

British Journal of Urology

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IntroductionCell death, or apoptosis, is not a single phenomenon but a series of morphologically and biochemically related processes [1,2]. Cell death of lymphocytes and other cells of reticulo-endothelial origin is dominated by changes in nuclear morphology [3], while apoptotic death of glandular epithelial cells, such as those of the prostate, requires profound cytoplasmic changes and alterations in the cell-cell and cell-substratum interactions [4]. The rodent prostate is a very useful model for the study of apoptosis induced by hormone withdrawal, The gland is an arborhed network of ducts, with several cell types that display anatomical and biochemical heterogeneity and substantially different sensitivities to androgen ablation. nor the basal cells that are also localized to the proximal region, appear to require androgens for survival. The prostate begins to regress about 12 h after castration, when the level of Sct-DHT falls below that needed to inhibit involution [lo]. The reduction in prostate size that occurs over the next 3-6 days is primarily due to the selective loss of the secretory luminal epithelial cells in the distal and intermediate regions, resulting in the complete obliteration of many of the ducts while maintaining the proximal segments of the ducts after castration. The process of apoptosis in the prostate can be broken down into several stages (Fig. 1). During the precondensation stage, many of the genes that are necessary for cell death are induced de now, or recruited from other functions in the gland. The length of the precondensation stage appears to vary from cell to cell and probably reflects the microheterogeneity in the hormone or growth factor environment. The precondensation phase is followed by cytoplasmic condensation which involves the loss of the interactions between the dying cell and its neighbours as the extra-cellular matrix (ECM) is degraded and the cytoplasmic volume decreases. During nuclear condensation, the activation of one or more endonucleases results in the fragmentation of the DNA and its marginalization to the nuclear periphery, Producing the hyperchromatic, pyknotic nucleus characteristic of apoptotic cells. As the initiation of apoptosis in glandular tissues is stochastic, it is difficult to separate clearly cytoplasmic and nuclear condensation temporally in vivo, but in isolated cells from other tissues (e.g. granulosal cells), nuclear condensation is clearly initiated after cytoplasmic condensation. During the fragmentation phase the apoptotic cell is subdivided into several apoptotic bodies which are subsequently phagocytosed by the neighbouring epithelial cells or macrophages and degraded by the lysosomal enzymes, activated either in the host cell or in the apoptotic body [l 11. Remarkably, this latter process occurs with no leakage of the intracelMar components into the extracellular space, ensuring that the complement cascade system is not activated and that there is no inflammatory response. This feature distinguishes apoptosis from necrosis. In the pr...

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Stefins and lysosomal cathepsins B, L and D in human breast carcinoma

Cited by 120 publications

References 27 publications

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

Cathepsin B, a Cysteine Protease Implicated in Metastatic Progression, is also Expressed During Regression of the Rat Prostate and Mammary Glands

Apoptosis, tumour invasion and prostate cancer

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