Summary
Cathepsin B has been linked to tumor progression through observations that its activity, secretion or membrane association are increased. The most malignant tumors, and specifically the cells at the invasive edge of those tumors, express the highest activity. Cathepsin B may facilitate invasion directly by dissolving extracellular matrix barriers like the basement membrane, or indirectly by activating other proteases capable of digesting the extracellular matrix. Cathepsin B also might play a role in tumor growth and angiogenesis. Cathepsin B activity is the result of several levels of regulation: transcription, post-transcrip-tional processing, translation and glycosylation, maturation and trafficking, and inhibition. The majority of reports on cathepsin B expression in tumors have focused on measurements of activity or protein staining. In some tumors, e.g., gliomas, a correlation between the amounts of cathepsin B mRNA, protein and activity and tumor progression has been established. Regulation of cathepsin B at the transcriptional and post-transcriptional levels is still poorly understood. Although the putative promoter regions have characteristics of housekeeping-type promoters, cathepsin B mRNA expression varies depending on the cell type and state of differentiation. We have evidence that more than one promoter could direct expression of human cathepsin B. Multiple transcript species have been detected, resulting from alternative splicing in the 5′- and 3′-untranslated regions, and possibly the use of alternative promoter regions. The existence of transcript variants indicates a potential for post-transcriptional control of expression. In support of this, ras-transformation of MCF-10A human breast epithelial cells results in an increase in protein levels without a concomitant increase in mRNA levels. Cathepsin B mRNA species with distinct 5′-or 3′-untranslated regions may differ in their stability and translatability. Variations in the coding region may also alter cathepsin B properties. We and Frankfater’s group have observed transcript species that would encode a truncated protein, lacking the prepeptide and about half of the propeptide. This truncated protein, if synthesized in cells, would be expected to be cytosolic; therefore its function is unclear. Once the several mechanisms of regulation of cathepsin B expression and activity are better understood, they could provide us with new strategies to specifically reduce cathepsin B activity in tumors.
Keywords
- Alternative Splice
- Transcript Variant
- Putative Promoter Region
- Human Breast Epithelial Cell
- Human Cathepsin
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Aronson, N.N., and Barrett, A.J., 1978, The specificity of cathepsin B, Biochem. J. 171:759–765.
Béchet, D.M., Ferrara, M.J., Mordier, S.B., Roux, M.-R, Deval, CD., and Obled, A., 1991, Expression of lysosomal cathepsin B during calf myoblast-myotube differentiation, J. Biol. Chem. 266:14104–14112.
Berquin, I.M., Cao, L., Fong, D., and Sloane, B.F., 1995, Identification of two new exons and multiple transcription start points in the 5′-untranslated region of the human cathepsin B-encoding gene, Gene 159: 143–149.
Buck, M.R., Karustis, D.G., Day, N.A., Honn, K.V., and Sloane, B.F., 1992, Degradation of extracellular-matrix proteins by human cathepsin B from normal and tumour tissues, Biochem. J. 282:2273–2278.
Cao, L., Taggart, R.T., Berquin, I.M., Moin, K., Fong, D., and Sloane, B.F., 1994, Human gastric adenocarcinoma cathepsin B: isolation and sequencing of full-length cDNAs and polymorphisms of the gene. Gene 139:163–169.
Campo, E., Munoz, J., Miquel, R., Palacin, A., Cardesa, A., Sloane, B.F., and Emmert-Buck, M., 1994, Cathepsin B expression in colorectal carcinomas correlates with tumor progression and shortened patient survival, Am. J. Pathol. 145: 301–309.
Cavaillès, V, Augereau, P., and Rochefort, H., 1993, Cathepsin D gene is controlled by a mixed promoter, and estrogens stimulate only TATA-dependent transcription in breast cancer cells, Proc. Natl. Acad. Sci. U.S.A. 90:203–207.
Chambers, A.F., Colella, R., Denhardt, D., and Wilson, S.M., 1992, Increased expression of cathepsin-L and cathepsin-B and decreased activity of their inhibitors in metastatic, ras-transformed NIH 3T3 cells, Mol. Carcinogen. 5:238–245.
Chan, S.J., San Segundo, B., McCormick, M.B., and Steiner, D.F., 1986, Nucleotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs, Proc. Natl. Acad. Sci. USA 83:7721–7725.
Colella, R., Rosen, F.J., and Bird, J.W., 1986, mRNA levels of cathepsin B and D during myogenesis, Biomed. Biochim. Acta 45:11–12.
Corticchiato, O., Cajot, J.-F., Abrahamson, M., Chan, S.J., Keppler, D., and Sordat, B., 1992, Cystatin C and cathepsin B in human colon carcinoma: expression by cell lines and matrix degradation, Intl. J. Cancer 52:645–652.
Dalet-Fumeron, V, Guinee, N., and Pagano, M., 1993, High-performance liquid chromatographic method for the simultaneous purification of cathepsins B, H and L from human liver, FEBS Lett. 332:251–254.
Emmert-Buck, M.R., Roth, M.J., Zhuang, Z., Campo, E., Rozhin, J., Sloane, B.F., Liotta, L.A., and Stetler-Stevenson, W.G., 1994, Increased gelatinase A (MMP-2) and cathepsin B activity in microdissected human colon cancer samples, Am. J. Pathol. 145, 1285–1290.
Ferrara, M., Wojcik, F., Rhaissi, H., Mordier, S., Roux, M.-R, and Béchet, D., 1990, Gene structure of mouse cathepsin B, FEBS Lett. 273:195–199.
Flaumenhaft, R., and Rifkin, D.B., 1992, The extracellular regulation of growth factor action, Mol. Biol. Cell 3:1057–1065.
Fong, D., Chan, M.M.-Y., Hsieh, W.-T., Menninger, J.C., and Ward, D.C., 1992, Confirmation of the human cathepsin B gene (CTSB) assignment to chromosome 8, Hum. Genet. 89:10–12.
Friemert, C, Closs, E.I., Silbermann, M., Erfle, V., and Strauss, P.G., 1991, Isolation of a cathepsin B-encoding cDNA from murine osteogenic cells, Gene 103:259–261.
Gong, Q., Chan, S.J., Bajkowski, A.S., Steiner, D.F., and Frankfater, A., 1993, Characterization of the cathepsin B gene and multiple mRNAs in human tissues: evidence for alternative splicing of cathepsin B pre-mRNA, DNA Cell Biol. 12:299–309.
Gong, Q., and Frankfater, A., 1993, Alternative splicing of cathepsin B in human tumors produces a novel isoform which can be refolded into an active enzyme in vitro, FASEB J. 7:A1208.
Huet, G., Flipo, R.-M., Colin, C, Janin, A., Hemon, B., Collyn-d’Hooge, M., Lafyatis, R., Duquesnoy, B., and Degand, P., 1993, Stimulation of the secretion of latent cysteine proteinase activity by tumor necrosis factor a and interleukin-1, Arthritis and Rheumatism 36:772–780.
Keppler, D., Abrahamson, M., and Sordat, B., 1994, Proteases and cancer: secretion of cathepsin B and tumour invasion, Biochem. Soc. Trans. 22:43–49.
Keppler, D., Waridel, P., Abrahamson, M., Bachmann, D., Berdoz, J., and Sordat, B., 1994, Latency of cathepsin B secreted by human colon carcinoma cells is not linked to secretion of cystatin C and is relieved by neutrophil elastase, Biochim. Biophys. Acta 1226:117–125.
Kobayashi, H., Schmitt, M., Goretzki, L., Chucholowski, N., Calvete, J., Kramer, M., Gunzler, W.A., Janicke, F., and Graeff, H., 1991, Cathepsin B efficiently activates the soluble and the tumor cell receptor-Cathepsin B Expression in Human Tumors 293 bound form of the proenzyme urokinase-type plasminogen activator (pro-uPA), J. Biol. Chem. 266:5147–5152.
Kornfeld, S., 1990, Lysosomal enzyme targeting, Biochem. Soc. Trans. 18:367–374.
Lah, T.T., Buck, M.R., Honn, K.V., Crissman, J.D., Rao, N.C., Liotta, L.A., and Sloane, B.F., 1989, Degradation of laminin by human tumor cathepsin B, Clin. Expl. Metastasis 7:461–468.
Matrisian, L.M., and Bowden, G.T., 1990, Stromelysin/transin and tumor progression, Semin. Cancer Biol. 1:107–115.
McIntyre, G.F., and Erickson, A.H., 1991, Procathepsins L and D are membrane-bound in acidic microsomal vesicles, J. Biol. Chem. 266:15438–15445.
Mikkelsen, T., Yan, P.-S., Ho, K.-L. Sameni, M., Sloane, B.F., and Rosenblum, M.L., 1995, Immunolocalization of cathepsin B in human glioma: implications for human tumor invasion and angiogenesis, J. Neurosurg.,83: 285–290.
Moin, K., Rozhin, J., McKernan, T.B., Sanders, V.J., Fong, D., Honn, K.V, and Sloane, B.F., 1989, Enhanced levels of cathepsin B mRNA in murine tumors, FEBS Lett. 244: 61–64.
Murnane, M.J., Sheahan, K., Ozdemirli, M., and Shuja, S., 1991, Stage-specific increases in cathepsin B messenger RNA content in human colorectal carcinoma, Cancer Res. 51:1137–1142.
Nguyen-Ba, G., Robert, S., Dhalluin, S., Tapiero, H., and Hornebeck, W., 1994. Modulatory effects of dexamethasone on ornithine decarboxylase activity and gene expression: a possible post-transcriptional regulation by a neutral metalloprotease. Cell Biochem. and Function 12:121–128.
Oursler, M.J., Riggs, B.L., and Speisberg, T.C., 1993, Glucocorticoid-induced activation of latent transforming growth factor-ß by normal human osteoblast-like cells. Endocrinology 133:2187–2196.
Page, A.E., Warburton, M.J., Chambers, T.J., Pringle, J.A.S., and Hayman, A.R., 1992, Human osteoclastomas contain multiple forms of cathepsin B. Biochim. Biophys. Acta 1116:57–66.
Petanceska, S., Burke, S., Watson, S.J. and Devi, L., 1994, Differential distribution of messenger RNAs for cathepsin B, L and S in adult rat brain: an in situ hybridization study. Neuroscience 59:729–738.
Phillips, I.D., Black, E.G., Sheppard, M.C., and Docherty, K., 1989, Thyrotrophin, forskolin and ionomycin increase cathepsin B mRNA concentration in rat thyroid cells in culture, J. Mol. Endocrinol. 2:207–212.
Qian, F., Bajkowski, A.S., Steiner, D.F., Chan, S.J., and Frankfater, A., 1989, Expression of five cathepsins in murine melanomas of varying metastatic potential and normal tissues, Cancer Res. 49:4870–4875.
Qian, F., Frankfater, A., Chan, S.J., and Steiner, D.F., 1991a, The structure of the mouse cathepsin B gene and its putative promoter, DNA Cell Biol. 10:159–168.
Qian, F., Frankfater, A., Steiner, D.F., Bajkowski, A.S., and Chan, S.J., 1991b, Characterization of multiple cathepsin B mRNAs in murine B16a melanoma, Anticancer Res. 11:1445–1452.
Qian, F., Chan, S.J., Achkar, C, Steiner, D.F. and Frankfater, A., 1994, Transcriptional regulation of cathepsin B expression in B16 melanomas of varying metastatic potential, Biochem. Biophys. Res. Comm. 202:429–436.
Rempel, S.A., Rosenblum, M.L., Mikkelsen. T., Yan, P.S., Ellis, K.D., Golembieski, W.A., Sameni, M., Rozhin, J., Ziegler, G., and Sloane, B.F., 1994, Cathepsin B expression and localization in glioma progression and invasion. Cancer Res. 54:6027–6031.
Rhaissi, H., Béchet, D., and Ferrara, M., 1993. Multiple leader sequences for mouse cathepsin B mRNA? Biochimie 75:899–904.
Sameni, M., Elliott, E., Ziegler, G., Fortgens, RH., Dennison, C, and Sloane, B.F., Cathepsins B and D are localized at surface of human breast cancer cells, Pathol. Oncol. Res., in press.
San Segundo, B., Chan, S.J., and Steiner, D.F., 1986, Differences in cathepsin B mRNA levels in rat tissues suggest specialized functions, FEBS Lett. 201:251–256.
Shuja, S., Sheahan, K., and Murnane, M.J., 1991, Cysteine endopeptidase activity levels in normal human tissues, colorectal adenomas and carcinomas, Intl. J. Cancer 49:341–346.
Sinha, A.A., Gleason, D.F., DeLeon, O.F., Wilson, M.J., and Sloane, B.F., 1993, Localization of a biotinylated cathepsin B oligonucleotide probe in human prostate including invasive cells and invasive edges by in situ hybridization, Anal. Rec. 235:233–240.
Sinha, A.A., Wilson, M.J., Gleason, D.F., Reddy, P.K., Sameni, M., and Sloane, B.F., 1995a, Immunohisto-chemical localization of cathepsin B in neoplastic human prostate, Prostate 25, 26: 171–178.
Sinha, A.A., Gleason, D.F., Staley, N.A., Wilson, M.J., Sameni, M., and Sloane, B.F., 1995b, Cathepsin B in angiogenesis of human prostate: an immunohistochemical and immunoelectron microscope analysis, Anat. Rec, 241: 353–262.
Sloane, B.F., Moin, K., Krepela, E., and Rozhin, J., 1990, Cathepsin B and its endogenous inhibitors: the role in tumor malignancy. Cancer Metastasis Reviews 9:333–352.
Sloane, B.R, Sameni, M., Cao, L., Berquin, I., Rozhin, J., Ziegler, G., Moin, K., and Day, N., 1994a, Alterations in processing and trafficking of cathepsin B during malignant progression, In Katunuma, N., Suzuki, K., Travis, J., and Fritz, H. (Eds) Biological Functions of Proteases and Inhibitors, Japan Scientific Societies Press, Tokyo, pp. 131–147.
Sloane, B.F., Moin, K., and Lah, T., 1994b, Regulation of lysosomal endopeptidases in malignant neoplasia, In Pretlow, T.G. and Pretlow, T.P. (Eds) Biochemical and Molecular Aspects of Selected Cancers, Vol. 2, Academic Press, San Diego, California, pp. 411–454.
Sloane, B.R, Moin, K., Sameni, M., Tait, L.R., Rozhin, J., and Ziegler, G., 1994c, Membrane association of cathepsin B can be induced by transfection of human breast epithelial cells with c-Ha-ras oncogene, J. Cell Science 107:373–384.
Tam, S.W., Cote-Paulino, L.R., Peak, D.A., Sheahan, K., and Murnane, M.J., 1994, Human cathepsin B cDNAs: sequence variations in the 3′-untranslated region, Gene 139:171–176.
Visscher, D.W., Sloane, B.F., Sameni, M., Babiarz, J.W., Jacobson, J. and Crissman, J.D., 1994, Clinico-pathologic significance of cathepsin B immunostaining in transitional neoplasia. Mod. Pathol. 7:76–81.
Wang, X., Chan, S.J., Eddy, R.L., Byers, M.G., Fukushima, Y., Henry, W.M., Haley, L.L., Steiner, D.F., and Shows, T.B., 1988, Chromosome assignment of cathepsin B (CTSB) to 8p22 and cathepsin H (CTSH) to 15q24–q25, Cytogenet. Cell Genet. 46:710–711.
Ward, C.J., Crocker, J., Chan, S.J., Stockley, R.A., and Burnett, D., 1990, Changes in the expression of elastase and cathepsin B with differentiation of U937 promonocytes by GMCSF, Biochem. Biophys. Res. Comm. 167:659–664.
Zhang, J.-Y, and Schultz, R.M., 1992, Fibroblasts transformed by different ras oncogenes show dissimilar patterns of protease gene expression and regulation, Cancer Res. 52:6682–6689.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Plenum Press, New York
About this chapter
Cite this chapter
Berquin, I.M., Sloane, B.F. (1996). Cathepsin B Expression in Human Tumors. In: Suzuki, K., Bond, J.S. (eds) Intracellular Protein Catabolism. Advances in Experimental Medicine and Biology, vol 389. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0335-0_35
Download citation
DOI: https://doi.org/10.1007/978-1-4613-0335-0_35
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-8003-0
Online ISBN: 978-1-4613-0335-0
eBook Packages: Springer Book Archive