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http://dx.doi.org/10.5483/BMBRep.2011.44.8.517

Niclosamide induces mitochondria fragmentation and promotes both apoptotic and autophagic cell death  

Park, So-Jung (Graduate School of East-West Medical Science, Kyung Hee University)
Shin, Ji-Hyun (Graduate School of East-West Medical Science, Kyung Hee University)
Kang, Hee (Graduate School of East-West Medical Science, Kyung Hee University)
Hwang, Jung-Jin (Institute for Innovative Cancer Research, Asan Medical Center)
Cho, Dong-Hyung (Graduate School of East-West Medical Science, Kyung Hee University)
Publication Information
BMB Reports / v.44, no.8, 2011 , pp. 517-522 More about this Journal
Abstract
Mitochondrial dynamics not only involves mitochondrial morphology but also mitochondrial biogenesis, mitochondrial distribution, and cell death. To identify specific regulators to mitochondria dynamics, we screened a chemical library and identified niclosamide as a potent inducer of mitochondria fission. Niclosamide promoted mitochondrial fragmentation but this was blocked by down-regulation of Drp1. Niclosamide treatment resulted in the disruption of mitochondria membrane potential and reduction of ATP levels. Moreover, niclosamide led to apoptotic cell death by caspase-3 activation. Interestingly, niclosamide also increased autophagic activity. Inhibition of autophagy suppressed niclosamide-induced cell death. Therefore, our findings suggest that niclosamide induces mitochondria fragmentation and may contribute to apoptotic and autophagic cell death.
Keywords
Apoptosis; Autophagy; Fission; Mitochondria dynamics; Niclosamide;
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Times Cited By Web Of Science : 4  (Related Records In Web of Science)
Times Cited By SCOPUS : 5
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1 Lim, M. L., Minamikawa, T. and Nagley, P. (2001) The protonophore CCCP induces mitochondrial permeability transition without cytochrome c release in human osteosarcoma cells. FEBS Lett. 503, 69-74.   DOI   ScienceOn
2 Legros, F., Lombès, A., Frachon, P. and Rojo, M. (2002) Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol. Biol. Cell 13, 4343-4354.   DOI   ScienceOn
3 Galluzzi, L., Larochette, N., Zamzami, N. and Kroemer, G. (2006) Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25, 4812-4830.   DOI   ScienceOn
4 Del Poeta, G., Bruno, A., Del Principe, M. I., Venditti, A., Maurillo, L., Buccisano, F., Stasi, R., Neri, B., Luciano, F., Siniscalchi, A., de Fabritiis, P. and Amadori, S. (2008) Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia. Curr. Cancer Drug Targets 8, 207-222.   DOI   ScienceOn
5 Edinger, A. L. and Thompson C. B. (2004) Death by design: apoptosis, necrosis and autophagy. Curr. Opin. Cell Biol. 16, 663-669.   DOI   ScienceOn
6 Galluzzi, L., Maiuri, M. C., Vitale, I., Zischka, H., Castedo, M., Zitvogel, L. and Kroemer, G. (2007) Cell death modalities: classification and pathophysiological implications. Cell Death Differ. 14, 1237-1243.   DOI   ScienceOn
7 Gies, E., Wilde, I., Winget, J. M., Brack, M., Rotblat, B., Novoa, C. A., Balgi, A. D., Sorensen, P. H., Roberge, M. and Mayor, T. (2010) Niclosamide prevents the formation of large ubiquitin-containing aggregates caused by proteasome inhibition. PLoS One 5, e14410.   DOI   ScienceOn
8 Jin, Y., Lu, Z., Ding, K., Li, J., Du, X., Chen, C., Sun, X., Wu, Y., Zhou, J. and Pan, J. (2010) Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-kappaB pathway and generation of reactive oxygen species. Cancer Res. 70, 2516-2527.   DOI
9 Park, J. P. and Fioravanti, C. F. (2006) Catalysis of NADH$\rightarrow$NADP+ transhydrogenation by adult Hymenolepis diminuta mitochondria. Parasitol. Res. 98, 200-206.   DOI
10 Balgi, A. D., Fonseca, B. D., Donohue, E., Tsang, T. C., Lajoie, P., Proud, C. G., Nabi, I. R. and Roberge, M. (2009) Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 22, e7124.
11 Zorzano, A., Sebastián, D., Segalés, J. and Palacín, M. (2009) The molecular machinery of mitochondrial fusion and fission: an opportunity for drug discovery. Curr. Opin. Drug Discov. Devel. 12, 597-606.
12 Hom, J. R., Gewandter, J. S., Michael, L., Sheu, S. S. and Yoon, Y. (2007) Thapsigargin induces biphasic fragmentation of mitochondria through calcium-mediated mitochondrial fission and apoptosis. J. Cell Physiol. 212, 498-508.   DOI   ScienceOn
13 Yoon, Y., Pitts, K. R. and McNiven, M. A. (2001) Mammalian dynamin-like protein DLP1 tubulates membranes. Mol. Biol. Cell 12, 2894-2905.   DOI
14 Gao, P., Bauvy, C., Souquère, S., Tonelli, G., Liu, L., Zhu, Y., Qiao, Z., Bakula, D., Proikas-Cezanne, T., Pierron, G., Codogno, P., Chen, Q. and Mehrpour, M. (2010) The Bcl-2 homology domain 3 mimetic gossypol induces both Beclin 1-dependent and Beclin 1-independent cytoprotective autophagy in cancer cells. J. Biol. Chem. 285, 2570-2581.
15 Chen, M., Wang, J., Lu, J., Bond, M. C., Ren, X. R., Lyerly, H. K., Barak, L. S. and Chen, W. (2009) The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry 48, 10267-10274.   DOI   ScienceOn
16 Dai, J. R., Coles, G. C., Wang, W. and Liang, Y. S. (2010) Toxicity of a novel suspension concentrate of niclosamide against Biomphalaria glabrata. Trans. R. Soc. Trop. Med. Hyg. 104, 304-306.   DOI   ScienceOn
17 Frank, S., Gaume, B., Bergmann-Leitner, E. S., Leitner, W. W., Robert, E. G., Catez, F., Smith, C. L. and Youle, R. J. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515-525.
18 Hoppins, S. and Nunnari, J. (2009) The molecular mechanism of mitochondrial fusion. Biochim. Biophys. Acta. 1793, 20-26.   DOI   ScienceOn
19 Olichon, A., Baricault, L., Gas, N., Guillou, E., Valette, A., Belenguer, P. and Lenaers, G. (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J. Biol. Chem. 278, 7743-7746.   DOI   ScienceOn
20 Suen, D. F., Norris, K. L. and Youle, R. J. (2008) Mitochondrial dynamics and apoptosis. Genes Dev. 22, 1577-1590.   DOI   ScienceOn
21 Gomes, L. C. and Scorrano, L. (2008) High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy. Biochim. Biophys. Acta. 1777, 860-866.   DOI   ScienceOn
22 Jeong, S. Y. and Seol, D. W. (2008) The role of mitochondria in apoptosis. BMB Rep. 41, 11-22.   DOI   ScienceOn
23 Twig, G., Elorza, A., Molina, A. J., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., Alroy, J., Wu, M., Py, B. F., Yuan, J., Deeney, J. T., Corkey, B. E. and Shirihai, O. S. (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433-446   DOI   ScienceOn
24 Cassidy-Stone, A., Chipuk, J. E., Ingerman, E., Song, C., Yoo, C., Kuwana, T., Kurth, M. J., Shaw, J. T., Hinshaw, J. E., Green, D. R. and Nunnari, J. (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev. Cell 14, 193-204.   DOI   ScienceOn
25 Yoon, Y. S., Yoon, D. S., Lim, I. K., Yoon, S. H., Chung, H. Y., Rojo, M., Malka, F., Jou, M. J., Martinou, J. C. and Yoon, G. S. (2006) Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1. Cell Physiol. 209, 468-480.   DOI   ScienceOn
26 Grandemange, S., Herzig, S. and Martinou, J. C. (2009) Mitochondrial dynamics and cancer. Semin. Cancer Biol. 19, 50-56.   DOI   ScienceOn
27 Liesa, M., Palacín, M. and Zorzano, A. (2009) Mitochondrial dynamics in mammalian health and disease. Physiol. Rev. 89, 799-845.   DOI   ScienceOn
28 Bossy-Wetzel, E., Barsoum, M. J., Godzik, A., Schwarzenbacher, R. and Lipton, S. A. (2003) Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr. Opin. Cell Biol. 15, 706-716.   DOI   ScienceOn
29 Chan, D. C. (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125, 1241-1252.   DOI   ScienceOn
30 Cho, D. H., Nakamura, T. and Lipton, S. A. (2010) Mitochondrial dynamics in cell death and neurodegeneration. Cell. Mol. Life Sci. 67, 3435-3447.   DOI
31 Smirnova, E., Griparic, L., Shurland, D. L. and van der Bliek, A. M. (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12, 2245-2256.   DOI