Cystatins as regulators of cancer
Main Article Content
Abstract
Abstract
The cystatins, natural inhibitors of cysteine proteases, act as metastasis suppressors for a wide variety of different cancers. An update of the various actions of cystatins in cancer is the focus of the current review. In the progression of cancer cells, besides certain genetic changes, augmentation of invasion occurs with an increase in cysteine protease (cathepsin) activity. Because the cystatins are key regulators of the cathepsins, they too play critical roles in cancer. All aspects of metastasis are influenced by the cystatins in a variety of cancers. For some cancers cystatins can be used as prognostic factors. New roles of the cystatins in cancer as gene regulatory proteins are being advanced. Overexpression of cystatins has been found to inhibit metastasis and angiogenesis in certain cancers. The cystatins may introduce future therapeutic advances in the control of cancer.
Keywords: cystatin, cathepsin, stefin, cancer, metastasis, cysteine protease inhibitor
Article Details
How to Cite
COX, James.
Cystatins as regulators of cancer.
Medical Research Archives, [S.l.], v. 5, n. 7, july 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1252>. Date accessed: 24 dec. 2024.
Keywords
medical, medicine,research,pharmacology
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
References
Alvarez-Diaz, S., N. Valle, J.M. Garcia, C. Pena, J.M. Freije, V. Quesada, A. Astudillo, F. Bonilla, C. Lopez-Otin, and A. Munoz. 2009. Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells. J Clin Invest. 119:2343-2358.
Anicin, A., N. Gale, L. Smid, J. Kos, and P. Strojan. 2013. Expression of stefin A is of prognostic significance in squamous cell carcinoma of the head and neck. Eur Arch Otorhinolaryngol. 270:3143-3151.
Bell-McGuinn, K.M., A.L. Garfall, M. Bogyo, D. Hanahan, and J.A. Joyce. 2007. Inhibition of cysteine cathepsin protease activity enhances chemotherapy regimens by decreasing tumor growth and invasiveness in a mouse model of multistage cancer. Cancer Res. 67:7378-7385.
Boutte, A.M., D.B. Friedman, M. Bogyo, Y. Min, L. Yang, and P.C. Lin. 2011. Identification of a myeloid-derived suppressor cell cystatin-like protein that inhibits metastasis. FASEB J. 25:2626-2637.
Butinar, M., M.T. Prebanda, J. Rajkovic, B. Jeric, V. Stoka, C. Peters, T. Reinheckel, A. Kruger, V. Turk, B. Turk, and O. Vasiljeva. 2014. Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model. Oncogene. 33:3392-3400.
Chen, J.C., B.J. Uang, P.C. Lyu, J.Y. Chang, K.J. Liu, C.C. Kuo, H.P. Hsieh, H.C. Wang, C.S. Cheng, Y.H. Chang, M.D. Chang, W.S. Chang, and C.C. Lin. 2010. Design and synthesis of alpha-ketoamides as cathepsin S inhibitors with potential applications against tumor invasion and angiogenesis. J Med Chem. 53:4545-4549.
Chen, Y.F., G. Ma, X. Cao, R.Z. Luo, L.R. He, J.H. He, Z.L. Huang, M.S. Zeng, and Z.S. Wen. 2013. Overexpression of cystatin SN positively affects survival of patients with surgically resected esophageal squamous cell carcinoma. BMC Surg. 13:15.
Choi, E.H., J.T. Kim, J.H. Kim, S.Y. Kim, E.Y. Song, J.W. Kim, S.Y. Kim, Y.I. Yeom, I.H. Kim, and H.G. Lee. 2009. Upregulation of the cysteine protease inhibitor, cystatin SN, contributes to cell proliferation and cathepsin inhibition in gastric cancer. Clin Chim Acta. 406:45-51.
Cox, J.L. 2009. Cystatins and cancer. Front Biosci (Landmark Ed). 14:463-474.
Droga-Mazovec, G., L. Bojic, A. Petelin, S. Ivanova, R. Romih, U. Repnik, G.S. Salvesen, V. Stoka, V. Turk, and B. Turk. 2008. Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. J Biol Chem. 283:19140-19150.
Ferrer-Mayorga, G., S. Alvarez-Diaz, N. Valle, J. De Las Rivas, M. Mendes, R. Barderas, F. Canals, O. Tapia, J.I. Casal, M. Lafarga, and A. Munoz. 2015. Cystatin D locates in the nucleus at sites of active transcription and modulates gene and protein expression. J Biol Chem. 290:26533-26548.
Gocheva, V., and J.A. Joyce. 2007. Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle. 6:60-64.
Gocheva, V., W. Zeng, D. Ke, D. Klimstra, T. Reinheckel, C. Peters, D. Hanahan, and J.A. Joyce. 2006. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev. 20:543-556.
Hunten, S., and H. Hermeking. 2015. p53 directly activates cystatin D/CST5 to mediate mesenchymal-epithelial transition: a possible link to tumor suppression by vitamin D3. Oncotarget. 6:15842-15856.
Jin, L., Y. Zhang, H. Li, L. Yao, D. Fu, X. Yao, L.X. Xu, X. Hu, and G. Hu. 2012. Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis. Cell Res. 22:1356-1373.
Kashuba, E., J. Bailey, D. Allsup, and L. Cawkwell. 2013a. The kinin-kallikrein system: physiological roles, pathophysiology and its relationship to cancer biomarkers. Biomarkers. 18:279-296.
Kashuba, E., G.L. Eagle, J. Bailey, P. Evans, K.J. Welham, D. Allsup, and L. Cawkwell. 2013b. Proteomic analysis of B-cell receptor signaling in chronic lymphocytic leukaemia reveals a possible role for kininogen. J Proteomics. 91:478-485.
Klose, A., P. Zigrino, R. Dennhofer, C. Mauch, and N. Hunzelmann. 2006. Identification and discrimination of extracellularly active cathepsins B and L in high-invasive melanoma cells. Anal Biochem. 353:57-62.
Li, C., L. Chen, J. Wang, L. Zhang, P. Tang, S. Zhai, W. Guo, N. Yu, L. Zhao, M. Liu, and S. Yang. 2011. Expression and clinical significance of cathepsin B and stefin A in laryngeal cancer. Oncol Rep. 26:869-875.
Lin, Y.Y., Z.W. Chen, Z.P. Lin, L.B. Lin, X.M. Yang, L.Y. Xu, and Q. Xie. 2016. Tissue Levels of Stefin A and Stefin B in Hepatocellular Carcinoma. Anat Rec (Hoboken). 299:428-438.
McIntire, S.a.J.C. 2015. The effect of cystatin C construct clones on B16F10 in vitro cell behavior. Journal of Molecular Biochemistry. 5.
Nishiyama, K., A. Konishi, C. Nishio, K. Araki-Yoshida, H. Hatanaka, M. Kojima, Y. Ohmiya, M. Yamada, and H. Koshimizu. 2005. Expression of cystatin C prevents oxidative stress-induced death in PC12 cells. Brain Res Bull. 67:94-99.
Olson, O.C., and J.A. Joyce. 2015. Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer. 15:712-729.
Pulukuri, S.M., B. Gorantla, J.A. Knost, and J.S. Rao. 2009. Frequent loss of cystatin E/M expression implicated in the progression of prostate cancer. Oncogene. 28:2829-2838.
Qiu, J., L. Ai, C. Ramachandran, B. Yao, S. Gopalakrishnan, C.R. Fields, A.L. Delmas, L.M. Dyer, S.J. Melnick, A.T. Yachnis, P.H. Schwartz, H.A. Fine, K.D. Brown, and K.D. Robertson. 2008. Invasion suppressor cystatin E/M (CST6): high-level cell type-specific expression in normal brain and epigenetic silencing in gliomas. Lab Invest. 88:910-925.
Rivenbark, A.G., and W.B. Coleman. 2009. Epigenetic regulation of cystatins in cancer. Front Biosci (Landmark Ed). 14:453-462.
Shree, T., O.C. Olson, B.T. Elie, J.C. Kester, A.L. Garfall, K. Simpson, K.M. Bell-McGuinn, E.C. Zabor, E. Brogi, and J.A. Joyce. 2011. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25:2465-2479.
Shridhar, R., J. Zhang, J. Song, B.A. Booth, C.G. Kevil, G. Sotiropoulou, B.F. Sloane, and D. Keppler. 2004. Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells. Oncogene. 23:2206-2215.
Small, D.M., R.E. Burden, J. Jaworski, S.M. Hegarty, S. Spence, J.F. Burrows, C. McFarlane, A. Kissenpfennig, H.O. McCarthy, J.A. Johnston, B. Walker, and C.J. Scott. 2013. Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization. Int J Cancer. 133:2102-2112.
Sotiropoulou, G., A. Anisowicz, and R. Sager. 1997. Identification, cloning, and characterization of cystatin M, a novel cysteine proteinase inhibitor, down-regulated in breast cancer. J Biol Chem. 272:903-910.
Strojan, P., A. Anicin, B. Svetic, L. Smid, and J. Kos. 2011. Proteolytic profile of cysteine proteases and inhibitors determines tumor cell phenotype in squamous cell carcinoma of the head and neck. Int J Biol Markers. 26:247-254.
Tang, N., Q. Xie, X. Wang, X. Li, Y. Chen, X. Lin, and J. Lin. 2011. Inhibition of invasion and metastasis of MHCC97H cells by expression of snake venom cystatin through reduction of proteinases activity and epithelial-mesenchymal transition. Arch Pharm Res. 34:781-789.
Turk, V., V. Stoka, and D. Turk. 2008. Cystatins: biochemical and structural properties, and medical relevance. Front Biosci. 13:5406-5420.
Wegiel, B., T. Jiborn, M. Abrahamson, L. Helczynski, L. Otterbein, J.L. Persson, and A. Bjartell. 2009. Cystatin C is downregulated in prostate cancer and modulates invasion of prostate cancer cells via MAPK/Erk and androgen receptor pathways. PLoS One. 4:e7953.
Weiss-Sadan, T., I. Gotsman, and G. Blum. 2017. Cysteine proteases in atherosclerosis. FEBS J.
Xie, Q., N. Tang, Y. Lin, X. Wang, X. Lin, and J. Lin. 2013a. Recombinant adenovirus snake venom cystatin inhibits the growth, invasion, and metastasis of B16F10 cells in vitro and in vivo. Melanoma Res. 23:444-451.
Xie, Q., N. Tang, R. Wan, Y. Qi, X. Lin, and J. Lin. 2013b. Recombinant snake venom cystatin inhibits tumor angiogenesis in vitro and in vivo associated with downregulation of VEGF-A165, Flt-1 and bFGF. Anticancer Agents Med Chem. 13:663-671.
Yan, Y., K. Zhou, L. Wang, Y. Zhou, X. Chen, and Q. Fan. 2015. Expression of cystatin C and its effect on EC9706 cells in esophageal carcinoma. Int J Clin Exp Pathol. 8:10102-10111.
Zajc, I., I. Hreljac, and T. Lah. 2006. Cathepsin L affects apoptosis of glioblastoma cells: a potential implication in the design of cancer therapeutics. Anticancer Res. 26:3357-3364.
Zhang, J., R. Shridhar, Q. Dai, J. Song, S.C. Barlow, L. Yin, B.F. Sloane, F.R. Miller, C. Meschonat, B.D. Li, F. Abreo, and D. Keppler. 2004. Cystatin m: a novel candidate tumor suppressor gene for breast cancer. Cancer Res. 64:6957-6964.
Alvarez-Diaz, S., N. Valle, J.M. Garcia, C. Pena, J.M. Freije, V. Quesada, A. Astudillo, F. Bonilla, C. Lopez-Otin, and A. Munoz. 2009. Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells. J Clin Invest. 119:2343-2358.
Anicin, A., N. Gale, L. Smid, J. Kos, and P. Strojan. 2013. Expression of stefin A is of prognostic significance in squamous cell carcinoma of the head and neck. Eur Arch Otorhinolaryngol. 270:3143-3151.
Bell-McGuinn, K.M., A.L. Garfall, M. Bogyo, D. Hanahan, and J.A. Joyce. 2007. Inhibition of cysteine cathepsin protease activity enhances chemotherapy regimens by decreasing tumor growth and invasiveness in a mouse model of multistage cancer. Cancer Res. 67:7378-7385.
Boutte, A.M., D.B. Friedman, M. Bogyo, Y. Min, L. Yang, and P.C. Lin. 2011. Identification of a myeloid-derived suppressor cell cystatin-like protein that inhibits metastasis. FASEB J. 25:2626-2637.
Butinar, M., M.T. Prebanda, J. Rajkovic, B. Jeric, V. Stoka, C. Peters, T. Reinheckel, A. Kruger, V. Turk, B. Turk, and O. Vasiljeva. 2014. Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model. Oncogene. 33:3392-3400.
Chen, J.C., B.J. Uang, P.C. Lyu, J.Y. Chang, K.J. Liu, C.C. Kuo, H.P. Hsieh, H.C. Wang, C.S. Cheng, Y.H. Chang, M.D. Chang, W.S. Chang, and C.C. Lin. 2010. Design and synthesis of alpha-ketoamides as cathepsin S inhibitors with potential applications against tumor invasion and angiogenesis. J Med Chem. 53:4545-4549.
Chen, Y.F., G. Ma, X. Cao, R.Z. Luo, L.R. He, J.H. He, Z.L. Huang, M.S. Zeng, and Z.S. Wen. 2013. Overexpression of cystatin SN positively affects survival of patients with surgically resected esophageal squamous cell carcinoma. BMC Surg. 13:15.
Choi, E.H., J.T. Kim, J.H. Kim, S.Y. Kim, E.Y. Song, J.W. Kim, S.Y. Kim, Y.I. Yeom, I.H. Kim, and H.G. Lee. 2009. Upregulation of the cysteine protease inhibitor, cystatin SN, contributes to cell proliferation and cathepsin inhibition in gastric cancer. Clin Chim Acta. 406:45-51.
Cox, J.L. 2009. Cystatins and cancer. Front Biosci (Landmark Ed). 14:463-474.
Droga-Mazovec, G., L. Bojic, A. Petelin, S. Ivanova, R. Romih, U. Repnik, G.S. Salvesen, V. Stoka, V. Turk, and B. Turk. 2008. Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. J Biol Chem. 283:19140-19150.
Ferrer-Mayorga, G., S. Alvarez-Diaz, N. Valle, J. De Las Rivas, M. Mendes, R. Barderas, F. Canals, O. Tapia, J.I. Casal, M. Lafarga, and A. Munoz. 2015. Cystatin D locates in the nucleus at sites of active transcription and modulates gene and protein expression. J Biol Chem. 290:26533-26548.
Gocheva, V., and J.A. Joyce. 2007. Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle. 6:60-64.
Gocheva, V., W. Zeng, D. Ke, D. Klimstra, T. Reinheckel, C. Peters, D. Hanahan, and J.A. Joyce. 2006. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev. 20:543-556.
Hunten, S., and H. Hermeking. 2015. p53 directly activates cystatin D/CST5 to mediate mesenchymal-epithelial transition: a possible link to tumor suppression by vitamin D3. Oncotarget. 6:15842-15856.
Jin, L., Y. Zhang, H. Li, L. Yao, D. Fu, X. Yao, L.X. Xu, X. Hu, and G. Hu. 2012. Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis. Cell Res. 22:1356-1373.
Kashuba, E., J. Bailey, D. Allsup, and L. Cawkwell. 2013a. The kinin-kallikrein system: physiological roles, pathophysiology and its relationship to cancer biomarkers. Biomarkers. 18:279-296.
Kashuba, E., G.L. Eagle, J. Bailey, P. Evans, K.J. Welham, D. Allsup, and L. Cawkwell. 2013b. Proteomic analysis of B-cell receptor signaling in chronic lymphocytic leukaemia reveals a possible role for kininogen. J Proteomics. 91:478-485.
Klose, A., P. Zigrino, R. Dennhofer, C. Mauch, and N. Hunzelmann. 2006. Identification and discrimination of extracellularly active cathepsins B and L in high-invasive melanoma cells. Anal Biochem. 353:57-62.
Li, C., L. Chen, J. Wang, L. Zhang, P. Tang, S. Zhai, W. Guo, N. Yu, L. Zhao, M. Liu, and S. Yang. 2011. Expression and clinical significance of cathepsin B and stefin A in laryngeal cancer. Oncol Rep. 26:869-875.
Lin, Y.Y., Z.W. Chen, Z.P. Lin, L.B. Lin, X.M. Yang, L.Y. Xu, and Q. Xie. 2016. Tissue Levels of Stefin A and Stefin B in Hepatocellular Carcinoma. Anat Rec (Hoboken). 299:428-438.
McIntire, S.a.J.C. 2015. The effect of cystatin C construct clones on B16F10 in vitro cell behavior. Journal of Molecular Biochemistry. 5.
Nishiyama, K., A. Konishi, C. Nishio, K. Araki-Yoshida, H. Hatanaka, M. Kojima, Y. Ohmiya, M. Yamada, and H. Koshimizu. 2005. Expression of cystatin C prevents oxidative stress-induced death in PC12 cells. Brain Res Bull. 67:94-99.
Olson, O.C., and J.A. Joyce. 2015. Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer. 15:712-729.
Pulukuri, S.M., B. Gorantla, J.A. Knost, and J.S. Rao. 2009. Frequent loss of cystatin E/M expression implicated in the progression of prostate cancer. Oncogene. 28:2829-2838.
Qiu, J., L. Ai, C. Ramachandran, B. Yao, S. Gopalakrishnan, C.R. Fields, A.L. Delmas, L.M. Dyer, S.J. Melnick, A.T. Yachnis, P.H. Schwartz, H.A. Fine, K.D. Brown, and K.D. Robertson. 2008. Invasion suppressor cystatin E/M (CST6): high-level cell type-specific expression in normal brain and epigenetic silencing in gliomas. Lab Invest. 88:910-925.
Rivenbark, A.G., and W.B. Coleman. 2009. Epigenetic regulation of cystatins in cancer. Front Biosci (Landmark Ed). 14:453-462.
Shree, T., O.C. Olson, B.T. Elie, J.C. Kester, A.L. Garfall, K. Simpson, K.M. Bell-McGuinn, E.C. Zabor, E. Brogi, and J.A. Joyce. 2011. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25:2465-2479.
Shridhar, R., J. Zhang, J. Song, B.A. Booth, C.G. Kevil, G. Sotiropoulou, B.F. Sloane, and D. Keppler. 2004. Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells. Oncogene. 23:2206-2215.
Small, D.M., R.E. Burden, J. Jaworski, S.M. Hegarty, S. Spence, J.F. Burrows, C. McFarlane, A. Kissenpfennig, H.O. McCarthy, J.A. Johnston, B. Walker, and C.J. Scott. 2013. Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization. Int J Cancer. 133:2102-2112.
Sotiropoulou, G., A. Anisowicz, and R. Sager. 1997. Identification, cloning, and characterization of cystatin M, a novel cysteine proteinase inhibitor, down-regulated in breast cancer. J Biol Chem. 272:903-910.
Strojan, P., A. Anicin, B. Svetic, L. Smid, and J. Kos. 2011. Proteolytic profile of cysteine proteases and inhibitors determines tumor cell phenotype in squamous cell carcinoma of the head and neck. Int J Biol Markers. 26:247-254.
Tang, N., Q. Xie, X. Wang, X. Li, Y. Chen, X. Lin, and J. Lin. 2011. Inhibition of invasion and metastasis of MHCC97H cells by expression of snake venom cystatin through reduction of proteinases activity and epithelial-mesenchymal transition. Arch Pharm Res. 34:781-789.
Turk, V., V. Stoka, and D. Turk. 2008. Cystatins: biochemical and structural properties, and medical relevance. Front Biosci. 13:5406-5420.
Wegiel, B., T. Jiborn, M. Abrahamson, L. Helczynski, L. Otterbein, J.L. Persson, and A. Bjartell. 2009. Cystatin C is downregulated in prostate cancer and modulates invasion of prostate cancer cells via MAPK/Erk and androgen receptor pathways. PLoS One. 4:e7953.
Weiss-Sadan, T., I. Gotsman, and G. Blum. 2017. Cysteine proteases in atherosclerosis. FEBS J.
Xie, Q., N. Tang, Y. Lin, X. Wang, X. Lin, and J. Lin. 2013a. Recombinant adenovirus snake venom cystatin inhibits the growth, invasion, and metastasis of B16F10 cells in vitro and in vivo. Melanoma Res. 23:444-451.
Xie, Q., N. Tang, R. Wan, Y. Qi, X. Lin, and J. Lin. 2013b. Recombinant snake venom cystatin inhibits tumor angiogenesis in vitro and in vivo associated with downregulation of VEGF-A165, Flt-1 and bFGF. Anticancer Agents Med Chem. 13:663-671.
Yan, Y., K. Zhou, L. Wang, Y. Zhou, X. Chen, and Q. Fan. 2015. Expression of cystatin C and its effect on EC9706 cells in esophageal carcinoma. Int J Clin Exp Pathol. 8:10102-10111.
Zajc, I., I. Hreljac, and T. Lah. 2006. Cathepsin L affects apoptosis of glioblastoma cells: a potential implication in the design of cancer therapeutics. Anticancer Res. 26:3357-3364.
Zhang, J., R. Shridhar, Q. Dai, J. Song, S.C. Barlow, L. Yin, B.F. Sloane, F.R. Miller, C. Meschonat, B.D. Li, F. Abreo, and D. Keppler. 2004. Cystatin m: a novel candidate tumor suppressor gene for breast cancer. Cancer Res. 64:6957-6964.