{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:58:01Z","timestamp":1791352681307,"version":"4.3.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,3,11]],"date-time":"2016-03-11T00:00:00Z","timestamp":1457654400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,3,11]],"date-time":"2016-03-11T00:00:00Z","timestamp":1457654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chloroquine (CQ), an anti-malarial drug, has immune-modulating activity and lysosomotropic activity. In this study, we investigated CQ sensitizes TRAIL-mediated apoptosis in human renal cancer Caki cells. Combination of CQ and TRAIL significantly induces apoptosis in human renal cancer Caki cells and various human cancer cells, but not in normal mouse kidney cells (TMCK-1) and human mesangial cells (MC). CQ up-regulates DR5 mRNA and protein expression in a dose- and time- dependent manner. Interestingly, CQ regulates DR5 expression through the increased stability in the mRNA and protein of DR5, rather than through the increased transcriptional activity of DR5. Moreover, we found that CQ decreased the expression of Cbl, an E3 ligase of DR5, and knock-down of Cbl markedly enhanced DR5 up-regulation. Other lysosomal inhibitors, including monensin and nigericin, also up-regulated DR5 and sensitized TRAIL-mediated apoptosis. Therefore, this study demonstrates that lysosomal inhibition by CQ may sensitize TRAIL-mediated apoptosis in human renal cancer Caki cells via DR5 up-regulation.<\/jats:p>","DOI":"10.1038\/srep22921","type":"journal-article","created":{"date-parts":[[2016,3,11]],"date-time":"2016-03-11T09:56:01Z","timestamp":1457690161000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Chloroquine enhances TRAIL-mediated apoptosis through up-regulation of DR5 by stabilization of mRNA and protein in cancer cells"],"prefix":"10.1038","volume":"6","author":[{"given":"Eun Jung","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoung-jin","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyeong Sook","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kubatka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kruzliak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Eun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taeg Kyu","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,3,11]]},"reference":[{"key":"BFsrep22921_CR1","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/S1074-7613(00)80212-5","volume":"12","author":"FC Kischkel","year":"2000","unstructured":"Kischkel, F. C. et al. Apo2L\/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12, 611\u2013620 (2000).","journal-title":"Immunity"},{"key":"BFsrep22921_CR2","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/sj.neo.7900203","volume":"3","author":"RK Srivastava","year":"2001","unstructured":"Srivastava, R. K. TRAIL\/Apo-2L: mechanisms and clinical applications in cancer. Neoplasia 3, 535\u2013546 (2001).","journal-title":"Neoplasia"},{"key":"BFsrep22921_CR3","doi-asserted-by":"publisher","first-page":"8628","DOI":"10.1038\/sj.onc.1207232","volume":"22","author":"S Wang","year":"2003","unstructured":"Wang, S. & El-Deiry, W. S. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22, 8628\u20138633 (2003).","journal-title":"Oncogene"},{"key":"BFsrep22921_CR4","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/S0014-5793(00)02042-1","volume":"482","author":"XD Zhang","year":"2000","unstructured":"Zhang, X. D., Nguyen, T., Thomas, W. D., Sanders, J. E. & Hersey, P. Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types. FEBS Lett 482, 193\u2013199 (2000).","journal-title":"FEBS Lett"},{"key":"BFsrep22921_CR5","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1074\/jbc.M608065200","volume":"282","author":"JJ Song","year":"2007","unstructured":"Song, J. J., An, J. Y., Kwon, Y. T. & Lee, Y. J. Evidence for two modes of development of acquired tumor necrosis factor-related apoptosis-inducing ligand resistance. Involvement of Bcl-xL. J Biol Chem 282, 319\u2013328 (2007).","journal-title":"J Biol Chem"},{"key":"BFsrep22921_CR6","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1038\/sj.cgt.7700792","volume":"12","author":"L Zhang","year":"2005","unstructured":"Zhang, L. & Fang, B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 12, 228\u2013237 (2005).","journal-title":"Cancer Gene Ther"},{"key":"BFsrep22921_CR7","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s12026-012-8284-8","volume":"52","author":"D Maksimovic-Ivanic","year":"2012","unstructured":"Maksimovic-Ivanic, D., Stosic-Grujicic, S., Nicoletti, F. & Mijatovic, S. Resistance to TRAIL and how to surmount it. Immunol Res 52, 157\u2013168 (2012).","journal-title":"Immunol Res"},{"key":"BFsrep22921_CR8","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.ejphar.2009.06.063","volume":"625","author":"VR Solomon","year":"2009","unstructured":"Solomon, V. R. & Lee, H. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 625, 220\u2013233 (2009).","journal-title":"Eur J Pharmacol"},{"key":"BFsrep22921_CR9","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.imlet.2013.07.004","volume":"153","author":"R Thome","year":"2013","unstructured":"Thome, R., Lopes, S. C., Costa, F. T. & Verinaud, L. Chloroquine: modes of action of an undervalued drug. Immunol Lett 153, 50\u201357 (2013).","journal-title":"Immunol Lett"},{"key":"BFsrep22921_CR10","doi-asserted-by":"publisher","first-page":"3218","DOI":"10.1016\/j.bmc.2005.12.035","volume":"14","author":"C Fan","year":"2006","unstructured":"Fan, C., Wang, W., Zhao, B., Zhang, S. & Miao, J. Chloroquine inhibits cell growth and induces cell death in A549 lung cancer cells. Bioorg Med Chem 14, 3218\u20133222 (2006).","journal-title":"Bioorg Med Chem"},{"key":"BFsrep22921_CR11","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1080\/07357900802427927","volume":"27","author":"Y Zheng","year":"2009","unstructured":"Zheng, Y. et al. Chloroquine inhibits colon cancer cell growth in vitro and tumor growth in vivo via induction of apoptosis. Cancer Invest 27, 286\u2013292 (2009).","journal-title":"Cancer Invest"},{"key":"BFsrep22921_CR12","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1159\/000185488","volume":"22","author":"PD Jiang","year":"2008","unstructured":"Jiang, P. D. et al. Cell growth inhibition, G2\/M cell cycle arrest, and apoptosis induced by chloroquine in human breast cancer cell line Bcap-37. Cell Physiol Biochem 22, 431\u2013440 (2008).","journal-title":"Cell Physiol Biochem"},{"key":"BFsrep22921_CR13","first-page":"768","volume":"16","author":"PD Jiang","year":"2008","unstructured":"Jiang, P. D. et al. [Effects of chloroquine diphosphate on proliferation and apoptosis of human leukemic K562 cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 16, 768\u2013771 (2008).","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"BFsrep22921_CR14","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1093\/neuonc\/nop046","volume":"12","author":"EL Kim","year":"2010","unstructured":"Kim, E. L. et al. Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells. Neuro Oncol 12, 389\u2013400 (2010).","journal-title":"Neuro Oncol"},{"key":"BFsrep22921_CR15","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.1038\/jid.2013.56","volume":"133","author":"AJ Lakhter","year":"2013","unstructured":"Lakhter, A. J. et al. Chloroquine promotes apoptosis in melanoma cells by inhibiting BH3 domain-mediated PUMA degradation. J Invest Dermatol 133, 2247\u20132254 (2013).","journal-title":"J Invest Dermatol"},{"key":"BFsrep22921_CR16","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1476-4598-12-16","volume":"12","author":"RL Zinn","year":"2013","unstructured":"Zinn, R. L. et al. Combination treatment with ABT-737 and chloroquine in preclinical models of small cell lung cancer. Mol Cancer 12, 16\u201325 (2013).","journal-title":"Mol Cancer"},{"key":"BFsrep22921_CR17","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1186\/1471-2407-10-370","volume":"10","author":"K Sasaki","year":"2010","unstructured":"Sasaki, K. et al. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer 10, 370\u2013380 (2010).","journal-title":"BMC Cancer"},{"key":"BFsrep22921_CR18","doi-asserted-by":"publisher","first-page":"200","DOI":"10.4161\/auto.8.2.18554","volume":"8","author":"P Maycotte","year":"2012","unstructured":"Maycotte, P. et al. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy 8, 200\u2013212 (2012).","journal-title":"Autophagy"},{"key":"BFsrep22921_CR19","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1097\/CAD.0b013e32835a36db","volume":"24","author":"S Enzenmuller","year":"2013","unstructured":"Enzenmuller, S., Gonzalez, P., Debatin, K. M. & Fulda, S. Chloroquine overcomes resistance of lung carcinoma cells to the dual PI3K\/mTOR inhibitor PI103 by lysosome-mediated apoptosis. Anticancer Drugs 24, 14\u201319 (2013).","journal-title":"Anticancer Drugs"},{"key":"BFsrep22921_CR20","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1002\/1097-0142(197309)32:3<536::AID-CNCR2820320304>3.0.CO;2-E","volume":"32","author":"SH Kim","year":"1973","unstructured":"Kim, S. H., Kim, J. H. & Fried, J. Enhancement of the radiation response of cultured tumor cells by chloroquine. Cancer 32, 536\u2013540 (1973).","journal-title":"Cancer"},{"key":"BFsrep22921_CR21","doi-asserted-by":"publisher","first-page":"267","DOI":"10.2307\/3578284","volume":"130","author":"B Djordjevic","year":"1992","unstructured":"Djordjevic, B., Lange, C. S., Austin, J. P. & Rotman, M. Potentiation of radiation lethality in HeLa cells by combined mild hyperthermia and chloroquine. Radiat Res 130, 267\u2013270 (1992).","journal-title":"Radiat Res"},{"key":"BFsrep22921_CR22","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1097\/00008390-199212000-00005","volume":"2","author":"B Djordevic","year":"1992","unstructured":"Djordevic, B., Lange, C. S. & Rotman, M. Potentiation of radiation lethality in mouse melanoma cells by mild hyperthermia and chloroquine. Melanoma Res 2, 321\u2013326 (1992).","journal-title":"Melanoma Res"},{"key":"BFsrep22921_CR23","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/S0022-3565(24)29450-7","volume":"298","author":"RJ Tallarida","year":"2001","unstructured":"Tallarida, R. J. Drug synergism: its detection and applications. J Pharmacol Exp Ther 298, 865\u2013872 (2001).","journal-title":"J Pharmacol Exp Ther"},{"key":"BFsrep22921_CR24","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/cgt.2012.88","volume":"20","author":"SY Kim","year":"2013","unstructured":"Kim, S. Y., Kim, J. H. & Song, J. J. c-Cbl shRNA-expressing adenovirus sensitizes TRAIL-induced apoptosis in prostate cancer DU-145 through increases of DR4\/5. Cancer Gene Ther 20, 82\u201387 (2013).","journal-title":"Cancer Gene Ther"},{"key":"BFsrep22921_CR25","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1097\/CAD.0b013e32835c0311","volume":"24","author":"EJ Park","year":"2013","unstructured":"Park, E. J., Choi, K. S., Yoo, Y. H. & Kwon, T. K. Nutlin-3, a small-molecule MDM2 inhibitor, sensitizes Caki cells to TRAIL-induced apoptosis through p53-mediated PUMA upregulation and ROS-mediated DR5 upregulation. Anticancer Drugs 24, 260\u2013269 (2013).","journal-title":"Anticancer Drugs"},{"key":"BFsrep22921_CR26","doi-asserted-by":"publisher","first-page":"2592","DOI":"10.1016\/j.yexcr.2011.08.005","volume":"317","author":"ES Yang","year":"2011","unstructured":"Yang, E. S., Woo, S. M., Choi, K. S. & Kwon, T. K. Acrolein sensitizes human renal cancer Caki cells to TRAIL-induced apoptosis via ROS-mediated up-regulation of death receptor-5 (DR5) and down-regulation of Bcl-2. Exp Cell Res 317, 2592\u20132601 (2011).","journal-title":"Exp Cell Res"},{"key":"BFsrep22921_CR27","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1158\/1535-7163.MCT-07-2368","volume":"7","author":"K Kandasamy","year":"2008","unstructured":"Kandasamy, K. & Kraft, A. S. Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3\u2032-untranslated region. Mol Cancer Ther 7, 1091\u20131100 (2008).","journal-title":"Mol Cancer Ther"},{"key":"BFsrep22921_CR28","doi-asserted-by":"publisher","first-page":"22426","DOI":"10.1074\/jbc.M110.149252","volume":"286","author":"N Myeku","year":"2011","unstructured":"Myeku, N. & Figueiredo-Pereira, M. E. Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: association with sequestosome 1\/p62. J Biol Chem 286, 22426\u201322440 (2011).","journal-title":"J Biol Chem"},{"key":"BFsrep22921_CR29","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.neulet.2009.03.085","volume":"456","author":"L Qiao","year":"2009","unstructured":"Qiao, L. & Zhang, J. Inhibition of lysosomal functions reduces proteasomal activity. Neurosci Lett 456, 15\u201319 (2009).","journal-title":"Neurosci Lett"},{"key":"BFsrep22921_CR30","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1007\/BF00444663","volume":"151","author":"S Doi","year":"1989","unstructured":"Doi, S., Tanabe, K., Watanabe, M. & Yoshimura, M. Chloroquine, a lysosomotropic agent, inhibits zygote formation in yeast. Arch Microbiol 151, 20\u201325 (1989).","journal-title":"Arch Microbiol"},{"key":"BFsrep22921_CR31","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1146\/annurev.pa.22.040182.002341","volume":"22","author":"BC Pressman","year":"1982","unstructured":"Pressman, B. C. & Fahim, M. Pharmacology and toxicology of the monovalent carboxylic ionophores. Annu Rev Pharmacol Toxicol 22, 465\u2013490 (1982).","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"BFsrep22921_CR32","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1146\/annurev.bi.45.070176.002441","volume":"45","author":"BC Pressman","year":"1976","unstructured":"Pressman, B. C. Biological applications of ionophores. Annu Rev Biochem 45, 501\u2013530 (1976).","journal-title":"Annu Rev Biochem"},{"key":"BFsrep22921_CR33","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1093\/carcin\/bgt137","volume":"34","author":"MJ Yoon","year":"2013","unstructured":"Yoon, M. J. et al. Monensin, a polyether ionophore antibiotic, overcomes TRAIL resistance in glioma cells via endoplasmic reticulum stress, DR5 upregulation and c-FLIP downregulation. Carcinogenesis 34, 1918\u20131928 (2013).","journal-title":"Carcinogenesis"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep22921.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep22921","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep22921.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T19:00:36Z","timestamp":1748804436000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep22921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,11]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,3,29]]}},"alternative-id":["BFsrep22921"],"URL":"https:\/\/doi.org\/10.1038\/srep22921","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,11]]},"assertion":[{"value":"17 December 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22921"}}