Browse > Article
http://dx.doi.org/10.5352/JLS.2021.31.5.527

The Functional Role of Lysosomes as Drug Resistance in Cancer  

Woo, Seon Min (Department of Immunology, School of Medicine, Keimyung University)
Kwon, Taeg Kyu (Department of Immunology, School of Medicine, Keimyung University)
Publication Information
Journal of Life Science / v.31, no.5, 2021 , pp. 527-535 More about this Journal
Abstract
Lysosomes are organelles surrounded by membranes that contain acid hydrolases; they degrade proteins, macromolecules, and lipids. According to nutrient conditions, lysosomes act as signaling hubs that regulate intracellular signaling pathways and are involved in the homeostasis of cells. Therefore, the lysosomal dysfunction occurs in various diseases, such as lysosomal storage disease, neurodegenerative diseases, and cancers. Multiple forms of stress can increase lysosomal membrane permeabilization (LMP), resulting in the induction of lysosome-mediated cell death through the release of lysosomal enzymes, including cathepsin, into the cytosol. Here we review the molecular mechanisms of LMP-mediated cell death and the enhancement of sensitivity to anticancer drugs. Induction of partial LMP increases apoptosis by releasing some cathepsins, whereas massive LMP and rupture induce non-apoptotic cell death through release of many cathepsins and generation of ROS and iron. Cancer cells have many drug-accumulating lysosomes that are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. Lysosomal sequestration of hydrophobic weak base anticancer drugs can have a significant impact on their subcellular distribution. Lysosome membrane damage by LMP can overcome resistance to anticancer drugs by freeing captured hydrophobic weak base drugs from lysosomes. Therefore, LMP inducers or lysosomotropic agents can regulate lysosomal integrity and are novel strategies for cancer therapy.
Keywords
Cancer therapy; cell death; drug resistance; lysosome; lysosomal membrane permeabilization;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Ballabio, A. and Bonifacino, J. S. 2020. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21, 101-118.   DOI
2 Chen, J. C., Uang, B. J., Lyu, P. C., Chang, J. Y., Liu, K. J., Kuo, C. C., Hsieh, H. P., Wang, H. C., Cheng, C. S., Chang, Y. H., Chang, M. D., Chang, W. S. and Lin, C. C. 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.   DOI
3 Boya, P. and Kroemer, G. 2008. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434-6451.   DOI
4 Bruchard, M., Mignot, G., Derangere, V., Chalmin, F., Chevriaux, A., Vegran, F., Boireau, W., Simon, B., Ryffel, B., Connat, J. L., Kanellopoulos, J., Martin, F., Rebe, C., Apetoh, L. and Ghiringhelli, F. 2013. Chemotherapy-triggered cathepsin b release in myeloid-derived suppressor cells activates the nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57-64.   DOI
5 Burgener, S. S., Leborgne, N. G. F., Snipas, S. J., Salvesen, G. S., Bird, P. I. and Benarafa, C. 2019. Cathepsin g inhibition by serpinb1 and serpinb6 prevents programmed necrosis in neutrophils and monocytes and reduces gsdmd-driven inflammation. Cell Rep. 27, 3646-3656.   DOI
6 de Duve, C., de Barsy, T., Poole, B., Trouet, A., Tulkens, P. and Van Hoof, F. 1974. Commentary. Lysosomotropic agents. Biochem. Pharmacol. 23, 2495-2531.   DOI
7 Burger, A. M., Jenkins, T. C., Double, J. A. and Bibby, M. C. 1999. Cellular uptake, cytotoxicity and DNA-binding studies of the novel imidazoacridinone antineoplastic agent c1311. Br. J. Cancer 81, 367-375.   DOI
8 Cesen, M. H., Pegan, K., Spes, A. and Turk, B. 2012. Lysosomal pathways to cell death and their therapeutic applications. Exp. Cell Res. 318, 1245-1251.   DOI
9 Chapuy, B., Koch, R., Radunski, U., Corsham, S., Cheong, N., Inagaki, N., Ban, N., Wenzel, D., Reinhardt, D., Zapf, A., Schweyer, S., Kosari, F., Klapper, W., Truemper, L. and Wulf, G. G. 2008. Intracellular abc transporter a3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 22, 1576-1586.   DOI
10 De Mei, C., Ercolani, L., Parodi, C., Veronesi, M., Lo Vecchio, C., Bottegoni, G., Torrente, E., Scarpelli, R., Marotta, R., Ruffili, R., Mattioli, M., Reggiani, A., Wade, M. and Grimaldi, B. 2015. Dual inhibition of rev-erbbeta and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells. Oncogene 34, 2597-2608.   DOI
11 Wang, J. H., Redmond, H. P., Watson, R. W. and Bouchier-Hayes, D. 1997. Induction of human endothelial cell apoptosis requires both heat shock and oxidative stress responses. Am. J. Physiol. 272, C1543-1551.   DOI
12 Seo, B. R., Min, K. J., Woo, S. M., Choe, M., Choi, K. S., Lee, Y. K., Yoon, G. and Kwon, T. K. 2017. 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. 27, 215-233.   DOI
13 Sudhan, D. R., Rabaglino, M. B., Wood, C. E. and Siemann, D. W. 2016. Cathepsin l in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor kgp94. Clin. Exp. Metastasis 33, 461-473.   DOI
14 Thelen, A. M. and Zoncu, R. 2017. Emerging roles for the lysosome in lipid metabolism. Trends Cell Biol. 27, 833-850.   DOI
15 Wang, F., Gomez-Sintes, R. and Boya, P. 2018. Lysosomal membrane permeabilization and cell death. Traffic 19, 918-931.   DOI
16 Wang, F., Zhang, Z., Leung, W. T., Chen, J., Yi, J., Ying, C., Yuan, M., Wang, M., Zhang, N., Qiu, X., Wang, L. and Wei, H. 2019. Hydroxychloroquine reverses the drug resistance of leukemic k562/adm cells by inhibiting autophagy. Mol. Med. Rep. 20, 3883-3892.
17 Yang, Y., Lim, S. K., Choong, L. Y., Lee, H., Chen, Y., Chong, P. K., Ashktorab, H., Wang, T. T., Salto-Tellez, M., Yeoh, K. G. and Lim, Y. P. 2010. Cathepsin s mediates gastric cancer cell migration and invasion via a putative network of metastasis-associated proteins. J. Proteome Res. 9, 4767-4778.   DOI
18 Yu, L., McPhee, C. K., Zheng, L., Mardones, G. A., Rong, Y., Peng, J., Mi, N., Zhao, Y., Liu, Z., Wan, F., Hailey, D. W., Oorschot, V., Klumperman, J., Baehrecke, E. H. and Lenardo, M. J. 2010. Termination of autophagy and reformation of lysosomes regulated by mtor. Nature 465, 942-946.   DOI
19 Zhang, L., Wang, H., Xu, J., Zhu, J. and Ding, K. 2014. Inhibition of cathepsin s induces autophagy and apoptosis in human glioblastoma cell lines through ros-mediated pi3k/akt/mtor/p70s6k and jnk signaling pathways. Toxicol. Lett. 228, 248-259.   DOI
20 Duvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., Vander Heiden, M. G., MacKeigan, J. P., Finan, P. M., Clish, C. B., Murphy, L. O. and Manning, B. D. 2010. Activation of a metabolic gene regulatory network downstream of mtor complex 1. Mol. Cell 39, 171-183.   DOI
21 Fairn, G. D. and Grinstein, S. 2012. How nascent phagosomes mature to become phagolysosomes. Trends Immunol. 33, 397-405.   DOI
22 Morgan, A. J., Platt, F. M., Lloyd-Evans, E. and Galione, A. 2011. Molecular mechanisms of endolysosomal ca2+ signalling in health and disease. Biochem. J. 439, 349-374.   DOI
23 Trivedi, P. C., Bartlett, J. J. and Pulinilkunnil, T. 2020. Lysosomal biology and function: Modern view of cellular debris bin. Cells 9, 1131-1165.   DOI
24 Zhang, Y., Liao, Z., Zhang, L. J. and Xiao, H. T. 2015. The utility of chloroquine in cancer therapy. Curr. Med. Res. Opin. 31, 1009-1013.   DOI
25 Molinari, A., Calcabrini, A., Meschini, S., Stringaro, A., Crateri, P., Toccacieli, L., Marra, M., Colone, M., Cianfriglia, M. and Arancia, G. 2002. Subcellular detection and localization of the drug transporter p-glycoprotein in cultured tumor cells. Curr. Protein Pept. Sci. 3, 653-670.   DOI
26 Nylandsted, J., Gyrd-Hansen, M., Danielewicz, A., Fehrenbacher, N., Lademann, U., Hoyer-Hansen, M., Weber, E., Multhoff, G., Rohde, M. and Jaattela, M. 2004. Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J. Exp. Med. 200, 425-435.   DOI
27 Park, E. J., Min, K. J., Choi, K. S., Kubatka, P., Kruzliak, P., Kim, D. E. and Kwon, T. K. 2016. Chloroquine enhances trail-mediated apoptosis through up-regulation of dr5 by stabilization of mrna and protein in cancer cells. Sci. Rep. 6, 22921.   DOI
28 Perera, R. M. and Zoncu, R. 2016. The lysosome as a regulatory hub. Annu. Rev. Cell Dev. Biol. 32, 223-253.   DOI
29 Ferrao, P., Sincock, P., Cole, S. and Ashman, L. 2001. Intracellular p-gp contributes to functional drug efflux and resistance in acute myeloid leukaemia. Leuk. Res. 25, 395-405.   DOI
30 Feng, Y., He, D., Yao, Z. and Klionsky, D. J. 2014. The machinery of macroautophagy. Cell Res. 24, 24-41.   DOI
31 Firestone, R. A., Pisano, J. M. and Bonney, R. J. 1979. Lysosomotropic agents. 1. Synthesis and cytotoxic action of lysosomotropic detergents. J. Med. Chem. 22, 1130-1133.   DOI
32 Gao, C., Ding, Y., Zhong, L., Jiang, L., Geng, C., Yao, X. and Cao, J. 2014. Tacrine induces apoptosis through lysosomeand mitochondria-dependent pathway in hepg2 cells. Toxicol. In Vitro 28, 667-674.   DOI
33 Goldman, S. D., Funk, R. S., Rajewski, R. A. and Krise, J. P. 2009. Mechanisms of amine accumulation in, and egress from, lysosomes. Bioanalysis 1, 1445-1459.   DOI
34 Saxton, R. A. and Sabatini, D. M. 2017. Mtor signaling in growth, metabolism, and disease. Cell 169, 361-371.   DOI
35 Platt, F. M. 2018. Emptying the stores: Lysosomal diseases and therapeutic strategies. Nat. Rev. Drug Discov. 17, 133-150.   DOI
36 Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S. and Sabatini, D. M. 2010. Ragulator-rag complex targets mtorc1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290-303.   DOI
37 Zhitomirsky, B. and Assaraf, Y. G. 2016. Lysosomes as mediators of drug resistance in cancer. Drug Resist. Updat. 24, 23-33.   DOI
38 Zhu, X., Sun, Y., Chen, D., Li, J., Dong, X., Wang, J., Chen, H., Wang, Y., Zhang, F., Dai, J., Pirraco, R. P., Guo, S., Marques, A. P., Reis, R. L. and Li, W. 2017. Mastocarcinoma therapy synergistically promoted by lysosome dependent apoptosis specifically evoked by 5-fu@nanogel system with passive targeting and ph activatable dual function. J. Control. Release 254, 107-118.   DOI
39 Huang, C. C., Chen, K. L., Cheung, C. H. A. and Chang, J. Y. 2013. Autophagy induced by cathepsin s inhibition induces early ros production, oxidative DNA damage, and cell death via xanthine oxidase. Free Radic. Biol. Med. 65, 1473-1486.   DOI
40 Guntuku, L., Gangasani, J. K., Thummuri, D., Borkar, R. M., Manavathi, B., Ragampeta, S., Vaidya, J. R., Sistla, R. and Vegi, N. G. M. 2019. Iitz-01, a novel potent lysosomotropic autophagy inhibitor, has single-agent antitumor efficacy in triple-negative breast cancer in vitro and in vivo. Oncogene 38, 581-595.   DOI
41 Serrano-Puebla, A. and Boya, P. 2016. Lysosomal membrane permeabilization in cell death: New evidence and implications for health and disease. Ann. N. Y. Acad. Sci. 1371, 30-44.   DOI
42 Zou, J., Kawai, T., Tsuchida, T., Kozaki, T., Tanaka, H., Shin, K. S., Kumar, H. and Akira, S. 2013. Poly ic triggers a cathepsin d- and ips-1-dependent pathway to enhance cytokine production and mediate dendritic cell necroptosis. Immunity 38, 717-728.   DOI
43 Seo, S. U., Min, K. J., Woo, S. M. and Kwon, T. K. 2018. Z-fl-cocho, a cathepsin s inhibitor, enhances oxaliplatin-mediated apoptosis through the induction of endoplasmic reticulum stress. Exp. Mol. Med. 50, 1-11.
44 Seo, S. U., Woo, S. M., Kim, M. W., Lee, H. S., Kim, S. H., Kang, S. C., Lee, E. W., Min, K. J. and Kwon, T. K. 2020. Cathepsin k inhibition-induced mitochondrial ros enhances sensitivity of cancer cells to anti-cancer drugs through usp27x-mediated bim protein stabilization. Redox Biol. 30, 101422.   DOI
45 Shachar, T., Lo Bianco, C., Recchia, A., Wiessner, C., RaasRothschild, A. and Futerman, A. H. 2011. Lysosomal storage disorders and parkinson's disease: Gaucher disease and beyond. Mov. Disord. 26, 1593-1604.   DOI
46 Shahriyar, S. A., Seo, S. U., Min, K. J., Kubatka, P., Min, D. S., Chang, J. S., Kim, D. E., Woo, S. M. and Kwon, T. K. 2020. Upregulation of dr5 and downregulation of survivin by iitz-01, lysosomotropic autophagy inhibitor, potentiates trail-mediated apoptosis in renal cancer cells via ubiquitin-proteasome pathway. Cancers (Basel) 12, 2363.   DOI
47 Torii, S., Shintoku, R., Kubota, C., Yaegashi, M., Torii, R., Sasaki, M., Suzuki, T., Mori, M., Yoshimoto, Y., Takeuchi, T. and Yamada, K. 2016. An essential role for functional lysosomes in ferroptosis of cancer cells. Biochem. J. 473, 769-777.   DOI
48 Zheng, X., Chu, F., Chou, P. M., Gallati, C., Dier, U., Mirkin, B. L., Mousa, S. A. and Rebbaa, A. 2009. Cathepsin l inhibition suppresses drug resistance in vitro and in vivo: A putative mechanism. Am. J. Physiol. Cell Physiol. 296, C65-74.   DOI
49 Sukhai, M. A., Prabha, S., Hurren, R., Rutledge, A. C., Lee, A. Y., Sriskanthadevan, S., Sun, H., Wang, X., Skrtic, M., Seneviratne, A., Cusimano, M., Jhas, B., Gronda, M., MacLean, N., Cho, E. E., Spagnuolo, P. A., Sharmeen, S., Gebbia, M., Urbanus, M., Eppert, K., Dissanayake, D., Jonet, A., Dassonville-Klimpt, A., Li, X., Datti, A., Ohashi, P. S., Wrana, J., Rogers, I., Sonnet, P., Ellis, W. Y., Corey, S. J., Eaves, C., Minden, M. D., Wang, J. C., Dick, J. E., Nislow, C., Giaever, G. and Schimmer, A. D. 2013. Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors. J. Clin. Invest. 123, 315-328.   DOI
50 Yamagishi, T., Sahni, S., Sharp, D. M., Arvind, A., Jansson, P. J. and Richardson, D. R. 2013. P-glycoprotein mediates drug resistance via a novel mechanism involving lysosomal sequestration. J. Biol. Chem. 288, 31761-31771.   DOI
51 Li, W. W., Li, J. and Bao, J. K. 2012. Microautophagy: Lesser-known self-eating. Cell. Mol. Life Sci. 69, 1125-1136.   DOI
52 Kagedal, K., Johansson, A. C., Johansson, U., Heimlich, G., Roberg, K., Wang, N. S., Jurgensmeier, J. M. and Ollinger, K. 2005. Lysosomal membrane permeabilization during apoptosis--involvement of bax? Int. J. Exp. Pathol. 86, 309-321.   DOI
53 Kagedal, K., Zhao, M., Svensson, I. and Brunk, U. T. 2001. Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem. J. 359, 335-343.   DOI
54 Kaur, J. and Debnath, J. 2015. Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461-472.   DOI
55 Manna, S. K., Zhang, H. J., Yan, T., Oberley, L. W. and Aggarwal, B. B. 1998. Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappab and activated protein-1. J. Biol. Chem. 273, 13245-13254.   DOI
56 Kaushik, S. and Cuervo, A. M. 2018. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol. 19, 365-381.   DOI
57 Li, M. 2018. Enzyme replacement therapy: A review and its role in treating lysosomal storage diseases. Pediatr. Ann. 47, e191-e197.   DOI
58 Li, P., Gu, M. and Xu, H. 2019. Lysosomal ion channels as decoders of cellular signals. Trends Biochem. Sci. 44, 110-124.   DOI
59 Logan, R., Funk, R. S., Axcell, E. and Krise, J. P. 2012. Drug-drug interactions involving lysosomes: Mechanisms and potential clinical implications. Expert Opin. Drug Metab. Toxicol. 8, 943-958.   DOI
60 Luzio, J. P., Parkinson, M. D., Gray, S. R. and Bright, N. A. 2009. The delivery of endocytosed cargo to lysosomes. Biochem. Soc. Trans. 37, 1019-1021.   DOI
61 Luzio, J. P., Pryor, P. R. and Bright, N. A. 2007. Lysosomes: Fusion and function. Nat. Rev. Mol. Cell Biol. 8, 622-632.   DOI
62 Luzio, J. P., Pryor, P. R., Gray, S. R., Gratian, M. J., Piper, R. C. and Bright, N. A. 2005. Membrane traffic to and from lysosomes. Biochem. Soc. Symp. 72, 77-86.   DOI
63 Assaraf, Y. G. 2006. The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis. Drug Resist. Updat. 9, 227-246.   DOI
64 Gillet, J. P. and Gottesman, M. M. 2011. Advances in the molecular detection of abc transporters involved in multidrug resistance in cancer. Curr. Pharm. Biotechnol. 12, 686-692.   DOI
65 Jensen, A. B., Wynne, C., Ramirez, G., He, W., Song, Y., Berd, Y., Wang, H., Mehta, A. and Lombardi, A. 2010. The cathepsin k inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: Results of a 4-week, double-blind, randomized, controlled trial. Clin. Breast Cancer 10, 452-458.   DOI
66 Mindell, J. A. 2012. Lysosomal acidification mechanisms. Annu. Rev. Physiol. 74, 69-86.   DOI
67 Liu, S., Li, Y., Choi, H. M. C., Sarkar, C., Koh, E. Y., Wu, J. and Lipinski, M. M. 2018. Lysosomal damage after spinal cord injury causes accumulation of ripk1 and ripk3 proteins and potentiation of necroptosis. Cell Death Dis. 9, 476.   DOI
68 Boya, P., Gonzalez-Polo, R. A., Poncet, D., Andreau, K., Vieira, H. L., Roumier, T., Perfettini, J. L. and Kroemer, G. 2003. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 22, 3927-3936.   DOI