Subscribe to RSS
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0041-1726151
Cysteine Cathepsins and Their Prognostic and Therapeutic Relevance in Leukemia
Funding Research in the laboratory of SSC is supported by research grants from Department of Science and Technology (India), Defence Research and Development Organisation (India), and Indian Council of Medical Research (India). M.A. is the recipient of SRF from Council of Scientific and Industrial Research (India).![](https://www.thieme-connect.de/media/10.1055-s-00044025/202102/lookinside/thumbnails/10.1055-s-0041-1726151-1.jpg)
Abstract
Cysteine cathepsins are lysosomal proteases that require Cys-His ion pair in their catalytic site for enzymatic activity. While their aberrant expression and oncogenic functions have been widely reported in solid tumors, recent findings suggest that these proteases also play an important role in the pathogenesis of hematological malignancies. In this review, we summarize the potential clinical implications of cysteine cathepsins as diagnostic and prognostic markers in leukemia, and present evidences which supports the utility of these proteases as potential therapeutic targets in hematological malignancies. We also highlight the available information on the expression patterns, regulation, and potential functions of cysteine cathepsins in normal hematopoiesis and hematological malignancies. In hematopoiesis, cysteine cathepsins play a variety of physiological roles including regulation of hematopoietic stem cell adhesion in the bone marrow, trafficking, and maturation. They are also involved in several functions of immune cells which include the selection of lymphocytes in the thymus, antigen processing, and presentation. However, the expression of cysteine cathepsins is dysregulated in hematological malignancies where they have been shown to play diverse functions. Interestingly, several pieces of evidence over the past few years have demonstrated overexpression of cathepsins in leukemia and their association with worst survival outcomes in patients. Strategies aimed at altering the expression, activity, and subcellular localization of these cathepsins are emerging as potential therapeutic modalaties in the management of hematological malignancies. Recent findings also suggest the involvement of these proteases in modulating the immune response in leukemia and lymphomas.
Publication History
Article published online:
13 April 2021
© 2021. National Academy of Medical Sciences (India). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
-
References
- 1 Conus S, Simon HU. Cathepsins and their involvement in immune responses. Swiss Med Wkly 2010; 140 (2930) w13042
- 2 Mathur PP, Grima J, Mo MY. et al. Differential expression of multiple cathepsin mRNAs in the rat testis during maturation and following lonidamine induced tissue restructuring. Biochem Mol Biol Int 1997; 42 (02) 217-233
- 3 Hook V, Funkelstein L, Lu D, Bark S, Wegrzyn J, Hwang S-R. Proteases for processing proneuropeptides into peptide neurotransmitters and hormones. Annu Rev Pharmacol Toxicol 2008; 48: 393-423
- 4 Carnevali O, Cionna C, Tosti L, Lubzens E, Maradonna F. Role of cathepsins in ovarian follicle growth and maturation. Gen Comp Endocrinol 2006; 146 (03) 195-203
- 5 Amarante-Paffaro AM, Hoshida MS, Yokota S. et al. Localization of cathepsins D and B at the maternal-fetal interface and the invasiveness of the trophoblast during the postimplantation period in the mouse. Cells Tissues Organs 2011; 193 (06) 417-425
- 6 Divya CP, Mahajan VS, Datta Gupta S, Chauhan SS. Differential activity of cathepsin L in human placenta at two different stages of gestation. Placenta 2002; 23 (01) 59-64
- 7 Zhao CF, Herrington DM. The function of cathepsins B, D, and X in atherosclerosis. Am J Cardiovasc Dis 2016; 6 (04) 163-170
- 8 Hashimoto Y, Kakegawa H, Narita Y. et al. Significance of cathepsin B accumulation in synovial fluid of rheumatoid arthritis. Biochem Biophys Res Commun 2001; 283 (02) 334-339
- 9 Edman MC, Janga SR, Meng Z. et al. Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren’s Syndrome patients. Sci Rep 2018; 8 (01) 11044
- 10 Koblinski J, Ahram M, Sloane B. Unraveling the Role of Proteases in Cancer. 2000 291.
- 11 Chauhan SS, Goldstein LJ, Gottesman MM. Expression of cathepsin L in human tumors. Cancer Res 1991; 51 (05) 1478-1481
- 12 Rawlings ND, Barrett AJ, Bateman A. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 2012; 40 (Database issue) D343-D350
- 13 Braulke T, Bonifacino JS. Sorting of lysosomal proteins. Biochim Biophys Acta 2009; 1793 (04) 605-614
- 14 Turk V, Stoka V, Vasiljeva O. et al. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta 2012; 1824 (01) 68-88
- 15 Choe Y, Leonetti F, Greenbaum DC. et al. Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities. J Biol Chem 2006; 281 (18) 12824-12832
- 16 Biniossek ML, Nägler DK, Becker-Pauly C, Schilling O. Proteomic identification of protease cleavage sites characterizes prime and non-prime specificity of cysteine cathepsins B, L, and S. J Proteome Res 2011; 10 (12) 5363-5373
- 17 Rudzińska M, Parodi A, Soond SM. et al. The role of cysteine cathepsins in cancer progression and drug resistance. Int J Mol Sci 2019; 20 (14) 3602
- 18 Pandey G, Bakhshi S, Thakur B, Jain P, Chauhan SS. Prognostic significance of cathepsin L expression in pediatric acute myeloid leukemia. Leuk Lymphoma 2018; 59 (09) 2175-2187
- 19 Pandey G, Bakhshi S, Kumar M. et al. Prognostic and therapeutic relevance of cathepsin B in pediatric acute myeloid leukemia. Am J Cancer Res 2019; 9 (12) 2634-2649
- 20 Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006; 25 (06) 977-988
- 21 Staudt ND, Aicher WK, Kalbacher H. et al. Cathepsin X is secreted by human osteoblasts, digests CXCL-12 and impairs adhesion of hematopoietic stem and progenitor cells to osteoblasts. Haematologica 2010; 95 (09) 1452-1460
- 22 Martino S, Tiribuzi R, Ciraci E. et al. Coordinated involvement of cathepsins S, D and cystatin C in the commitment of hematopoietic stem cells to dendritic cells. Int J Biochem Cell Biol 2011; 43 (05) 775-783
- 23 Kos J, Jevnikar Z, Obermajer N. The role of cathepsin X in cell signaling. Cell Adhes Migr 2009; 3 (02) 164-166
- 24 Lalanne AI, Moraga I, Hao Y. et al. CpG inhibits pro-B cell expansion through a cathepsin B-dependent mechanism. J Immunol 2010; 184 (10) 5678-5685
- 25 Honey K, Rudensky AY. Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol 2003; 3 (06) 472-482
- 26 Hsing LC, Rudensky AY. The lysosomal cysteine proteases in MHC class II antigen presentation. Immunol Rev 2005; 207 (01) 229-241
- 27 Shi G-P, Bryant RA, Riese R. et al. Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages. J Exp Med 2000; 191 (07) 1177-1186
- 28 Driessen C, Lennon-Duménil A-M, Ploegh HL. Individual cathepsins degrade immune complexes internalized by antigen-presenting cells via Fcgamma receptors. Eur J Immunol 2001; 31 (05) 1592-1601
- 29 Tolosa E, Li W, Yasuda Y. et al. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J Clin Invest 2003; 112 (04) 517-526
- 30 Stoeckle C, Quecke P, Rückrich T. et al. Cathepsin S dominates autoantigen processing in human thymic dendritic cells. J Autoimmun 2012; 38 (04) 332-343
- 31 Stoeckle C, Gouttefangeas C, Hammer M, Weber E, Melms A, Tolosa E. Cathepsin W expressed exclusively in CD8+ T cells and NK cells, is secreted during target cell killing but is not essential for cytotoxicity in human CTLs. Exp Hematol 2009; 37 (02) 266-275
- 32 Jakoš T, Pišlar A, Jewett A, Kos J. Cysteine cathepsins in tumor-associated immune cells. Front Immunol 2019; 10: 2037
- 33 Tan G, Liu Q, Tang X. et al. Diagnostic values of serum cathepsin B and D in patients with nasopharyngeal carcinoma. BMC Cancer 2016; 16: 241
- 34 Liu W-L, Liu D, Cheng K. et al. Evaluating the diagnostic and prognostic value of circulating cathepsin S in gastric cancer. Oncotarget 2016; 7 (19) 28124-28138
- 35 Kehlet SN, Bager CL, Willumsen N. et al. Cathepsin-S degraded decorin are elevated in fibrotic lung disorders - development and biological validation of a new serum biomarker. BMC Pulm Med 2017; 17 (01) 110
- 36 Kothapalli R, Bailey RD, Kusmartseva I. Mane S, Epling-Burnette PK, Loughran TP Jr. Constitutive expression of cytotoxic proteases and down-regulation of protease inhibitors in LGL leukemia. Int J Oncol 2003; 22 (01) 33-39
- 37 Jain M, Bakhshi S, Shukla AA, Chauhan SS. Cathepsins B and L in peripheral blood mononuclear cells of pediatric acute myeloid leukemia: potential poor prognostic markers. Ann Hematol 2010; 89 (12) 1223-1232
- 38 Chauhan SS, Popescu NC, Ray D, Fleischmann R, Gottesman MM, Troen BR. Cloning, genomic organization, and chromosomal localization of human cathepsin L. J Biol Chem 1993; 268 (02) 1039-1045
- 39 Albano F, Specchia G, Anelli L. et al. Genomic deletions on other chromosomes involved in variant t(9;22) chronic myeloid leukemia cases. Genes Chromosomes Cancer 2003; 36 (04) 353-360
- 40 Samaiya M, Bakhshi S, Shukla AA, Kumar L, Chauhan SS. Epigenetic regulation of cathepsin L expression in chronic myeloid leukaemia. J Cell Mol Med 2011; 15 (10) 2189-2199
- 41 Keerthivasan S, Keerthivasan G, Mittal S, Chauhan SS. Tran-scriptional upregulation of human cathepsin L by VEGF in glioblastoma cells. Gene 2007; 399 (02) 129-136
- 42 Wrona E, Jakubowska J, Pawlik B. et al. Gene expression of ASNS, LGMN and CTSB is elevated in a subgroup of childhood BCP-ALL with PAX5 deletion. Oncol Lett 2019; 18 (06) 6926-6932
- 43 Löser R, Pietzsch J. Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes. Front Chem 2015; 3: 37
- 44 Habibollahi P, Figueiredo J-L, Heidari P. et al. Optical imaging with a cathepsin B activated probe for the enhanced detection of esophageal adenocarcinoma by dual channel fluorescent upper GI endoscopy. Theranostics 2012; 2 (02) 227-234
- 45 Ma W, Ma L, Zhe H. et al. Detection of esophageal squamous cell carcinoma by cathepsin B activity in nude mice. PLoS ONE 2014; 9 (03) e92351
- 46 Kozloff KM, Quinti L, Patntirapong S. et al. Non-invasive optical detection of cathepsin K-mediated fluorescence reveals osteoclast activity in vitro and in vivo. Bone 2009; 44 (02) 190-198
- 47 Lai W-FT, Chang C-H, Tang Y, Bronson R, Tung C-H. Early diagnosis of osteoarthritis using cathepsin B sensitive near-infrared fluorescent probes. Osteoarthritis Cartilage 2004; 12 (03) 239-244
- 48 Scales HE, Ierna M, Smith KM. et al. Assessment of murine collagen-induced arthritis by longitudinal non-invasive duplexed molecular optical imaging. Rheumatology (Oxford) 2016; 55 (03) 564-572
- 49 Li Y-Y, Fang J, Ao G-Z. Cathepsin B and L inhibitors: a patent review (2010 - present).. Expert Opin Ther Pat 2017; 27 (06) 643-656
- 50 Schmitz J, Gilberg E, Löser R, Bajorath J, Bartz U, Gütschow M. Cathepsin B: active site mapping with peptidic substrates and inhibitors. Bioorg Med Chem 2019; 27 (01) 1-15
- 51 Poreba M, Rut W, Vizovisek M. et al. Selective imaging of cathepsin L in breast cancer by fluorescent activity-based probes. Chem Sci (Camb) 2018; 9 (08) 2113-2129
- 52 Yuan L, Sheng L, He W. et al. Discovery of novel cathepsin inhibitors with potent anti-metastatic effects in breast cancer cells. Bioorg Chem 2018; 81: 672-680
- 53 Nalla AK, Gorantla B, Gondi CS, Lakka SS, Rao JS. Targeting MMP-9, uPAR, and cathepsin B inhibits invasion, migration and activates apoptosis in prostate cancer cells. Cancer Gene Ther 2010; 17 (09) 599-613
- 54 Jung M, Lee J, Seo H-Y, Lim JS, Kim E-K. Cathepsin inhibition-induced lysosomal dysfunction enhances pancreatic beta-cell apoptosis in high glucose. PLoS One 2015; 10 (01) e0116972
- 55 Soond SM, Kozhevnikova MV, Townsend PA, Zamyatnin Jr AA. Cysteine cathepsin protease inhibition: an update on its diagnostic, prognostic and therapeutic potential in cancer. Pharmaceuticals (Basel) 2019; 12 (02) 87
- 56 Ward C, Kuehn D, Burden RE. et al. Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF. PLoS One 2010; 5 (09) e12543
- 57 Seo BR, Min K-J, Woo SM. et al. Inhibition of cathepsin S induces mitochondrial ROS that sensitizes TRAIL-mediated apoptosis through p53-mediated downregulation of Bcl-2 and c-FLIP. Antioxid Redox Signal 2017; 27 (04) 215-233
- 58 Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci 2019; 26 (01) 78
- 59 Bengsch F, Buck A, Günther SC. et al. Cell type-dependent pathogenic functions of overexpressed human cathepsin B in murine breast cancer progression. Oncogene 2014; 33 (36) 4474-4484
- 60 Shree T, Olson OC, Elie BT. et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 2011; 25 (23) 2465-2479
- 61 Salpeter SJ, Pozniak Y, Merquiol E, Ben-Nun Y, Geiger T, Blum G. A novel cysteine cathepsin inhibitor yields macrophage cell death and mammary tumor regression. Oncogene 2015; 34 (50) 6066-6078
- 62 van der Meer LT, Waanders E, Levers M. et al. A germ line mutation in cathepsin B points toward a role in asparaginase pharmacokinetics. Blood 2014; 124 (19) 3027-3029
- 63 Patel N, Krishnan S, Offman MN. et al. A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase. J Clin Invest 2009; 119 (07) 1964-1973
- 64 Zhu D-M, Uckun FM. Cathepsin inhibition induces apoptotic death in human leukemia and lymphoma cells. Leuk Lymphoma 2000; 39 (3-4) 343-354
- 65 Liow KY, Chow SC. The cathepsin B inhibitor z-FA-CMK induces cell death in leukemic T cells via oxidative stress. Naunyn Schmiedebergs Arch Pharmacol 2018; 391 (01) 71-82
- 66 Liow KY, Chow SC. The cathepsin B inhibitor, z-FA-CMK is toxic and readily induced cell death in human T lymphocytes. Toxicol Appl Pharmacol 2013; 272 (03) 559-567
- 67 Ivanov A, Beers SA, Walshe CA. et al. Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells. J Clin Invest 2009; 119 (08) 2143-2159
- 68 Puissant A, Dufies M, Raynaud S, Cassuto J-P, Auberger P. Targeting lysosomes to eradicate imatinib-resistant chronic myelogenous leukemia cells. Leukemia 2010; 24 (05) 1099-1101
- 69 Yoon J-Y, Szwajcer D, Ishdorj G. et al. Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B. Blood Cancer J 2013; 3 (10) e153-e153
- 70 Zhang M, Sukhumalchandra P, Enyenihi AA. et al. A novel HLA-A*0201 restricted peptide derived from cathepsin G is an effective immunotherapeutic target in acute myeloid leukemia. Clin Cancer Res 2013; 19 (01) 247-257
- 71 Monsouvanh A, Proungvitaya T, Limpaiboon T. et al. Serum cathepsin B to cystatin C ratio as a potential marker for the diagnosis of cholangiocarcinoma. Asian Pac J Cancer Prev 2014; 15 (21) 9511-9515
- 72 Zore I, Krasovec M, Cimerman N. et al. Cathepsin B/cystatin C complex levels in sera from patients with lung and colorectal cancer. Biol Chem 2001; 382 (05) 805-810