Inhibition of BMI1 induces autophagy-mediated necroptosis
Open accessAbstract
The clonal self-renewal property conferred by BMI1 is instrumental in maintenance of not only normal stem cells but also cancer-initiating cells from several different malignancies that represent a major challenge to chemotherapy. Realizing the immense pathological significance, PTC-209, a small molecule inhibitor of BMI1 transcription has recently been described. While targeting BMI1 in various systems significantly decreases clonal growth, the mechanisms differ, are context-dependent, and somewhat unclear. We report here that genetic or pharmacological inhibition of BMI1 significantly impacts clonal growth without altering CDKN2A/INK4/ARF or CCNG2 and induces autophagy in ovarian cancer (OvCa) cells through ATP depletion. While autophagy can promote survival or induce cell death, targeting BMI1 engages the PINK1-PARK2-dependent mitochondrial pathway and induces a novel mode of nonapoptotic, necroptosis-mediated cell death. In OvCa, necroptosis is potentiated by activation of the RIPK1-RIPK3 complex that phosphorylates its downstream substrate, MLKL. Importantly, genetic or pharmacological inhibitors of autophagy or RIPK3 rescue clonal growth in BMI1 depleted cells. Thus, we have established a novel molecular link between BMI1, clonal growth, autophagy and necroptosis. In chemoresistant OvCa where apoptotic pathways are frequently impaired, necroptotic cell death modalities provide an important alternate strategy that leverage overexpression of BMI1.
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Necroptosis is favored by a necrosome-scaffolding function of the autophagy apparatus and by autophagic degradation of c-IAP1 and c-IAP2.
“necroptosis, which is favored by a necrosome-scaffolding function of the autophagy apparatus [823–825], as well as by the autophagic degradation of c-IAP1 and c-IAP2 [826].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [824]
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Cites
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · see citing works
Cui, C., Cui, J., Jin, F., Cui, Y., Li, R., Jiang, X., Tian, Y., Wang, R. C., Jiang, P., & Gao, J. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479571 · Cited by 5,214 · see citing works
Oxyl radicals, redox-sensitive signalling cascades and antioxidants
Genestra, M. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.04.009 · Cited by 4,930 · see citing works
Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G., & Johansen, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702824200 · Cited by 4,578 · see citing works
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497 · see citing works
Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000) · Cell · doi:10.1016/s0092-8674(00)00008-8 · Cited by 3,513 · see citing works
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601963 · Cited by 3,082 · see citing works
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D.-F., Gautier, C. A., Shen, J., Cookson, M. R., & Youle, R. J. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000298 · Cited by 2,944 · see citing works
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Geisler, S., Holmström, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., & Springer, W. (2010) · Nature Cell Biology · doi:10.1038/ncb2012 · Cited by 2,835 · see citing works
Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase
Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.031 · Cited by 2,698 · see citing works
Autophagy in Health and Disease: A Double-Edged Sword
Shintani, T., & Klionsky, D. J. (2004) · Science · doi:10.1126/science.1099993 · Cited by 2,531 · see citing works
Cho, Y., Challa, S., Moquin, D., Genga, R., Ray, T. D., Guildford, M., & Chan, F. K.-M. (2009) · Cell · doi:10.1016/j.cell.2009.05.037 · Cited by 2,435 · see citing works
Molecular mechanisms of necroptosis: an ordered cellular explosion
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T., & Kroemer, G. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2970 · Cited by 2,382 · see citing works
AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy
Hardie, D. G. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2249 · Cited by 2,207 · see citing works
Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
Komatsu, M., Waguri, S., Koike, M., Sou, Y.-S., Ueno, T., Hara, T., Mizushima, N., Iwata, J.-I., Ezaki, J., Murata, S., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.035 · Cited by 2,124 · see citing works
Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C. A., Sou, Y.-S., Saiki, S., Kawajiri, S., Sato, F., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200910140 · Cited by 1,969 · see citing works
Role of histone H2A ubiquitination in Polycomb silencing
Wang, H., Wang, L., Erdjument‐Bromage, H., Vidal, M., Tempst, P., Jones, R. S., & Zhang, Y. (2004) · Nature · doi:10.1038/nature02985 · Cited by 1,770 · see citing works
Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks
Alers, S., Löffler, A. S., Wesselborg, S., & Stork, B. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06159-11 · Cited by 1,483 · see citing works
Lemasters, J. J., Nieminen, A.-L., Qian, T., Trost, L. C., Elmore, S. P., Nishimura, Y., Crowe, R. A., Cascio, W. E., Bradham, C. A., Brenner, D. A., et al. (1998) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(98)00112-1 · Cited by 1,387 · see citing works
Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis
Cai, Z., Jitkaew, S., Zhao, J., Chiang, H.-C., Choksi, S., Liu, J., Ward, Y., Wu, L.-G., & Liu, Z.-G. (2014) · Nature Cell Biology · doi:10.1038/ncb2883 · Cited by 1,322 · see citing works
Yamamoto, A., Tagawa, Y., Yoshimori, T., Moriyama, Y., Masaki, R., & Tashiro, Y. (1998) · Cell Structure and Function · doi:10.1247/csf.23.33 · Cited by 1,312 · see citing works
Li, J., McQuade, T., Siemer, A. B., Napetschnig, J., Moriwaki, K., Hsiao, Y.-S., Damko, E., Moquin, D., Walz, T., McDermott, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.019 · Cited by 1,222 · see citing works
Regulation of an ATG7 - beclin 1 Program of Autophagic Cell Death by Caspase-8
Yu, L., Alva, A. S., Su, H. C., Dutt, P., Freundt, E. C., Welsh, S. J., Baehrecke, E. H., & Lenardo, M. J. (2004) · Science · doi:10.1126/science.1096645 · Cited by 1,220 · see citing works
Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts
Frezza, C., Cipolat, S., & Scorrano, L. (2007) · Nature Protocols · doi:10.1038/nprot.2006.478 · Cited by 1,188 · see citing works
Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL
Kaiser, W. J., Sridharan, H., Huang, C., Mandal, P., Upton, J. W., Gough, P. J., Sehon, C. A., Marquis, R. W., Bertin, J., & Mocarski, E. S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.462341 · Cited by 959 · see citing works
Wang, Z., Jiang, H., Chen, S., Du, F., & Wang, X. (2012) · Cell · doi:10.1016/j.cell.2011.11.030 · Cited by 949 · see citing works
Bolster, D. R., Crozier, S. J., Kimball, S. R., & Jefferson, L. S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200171200 · Cited by 851 · see citing works
Role of Bmi-1 and Ring1A in H2A Ubiquitylation and Hox Gene Silencing
Cao, R., Tsukada, Y.-I., & Zhang, Y. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.12.002 · Cited by 847 · see citing works
Kubli, D. A., & Gustafsson, Å. B. (2012) · Circulation Research · doi:10.1161/circresaha.112.265819 · Cited by 792 · see citing works
Necroptosis as an alternative form of programmed cell death
Christofferson, D. E., & Yuan, J. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.12.003 · Cited by 771 · see citing works
Hanna, R. A., Quinsay, M. N., Orogo, A. M., Giang, K., Rikka, S., & Gustafsson, Å. B. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.322933 · Cited by 762 · see citing works
Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment
Greene, A. W., Grenier, K., Aguileta, M. A., Muise, S., Farazifard, R., Haque, M. E., McBride, H. M., Park, D. S., & Fon, E. A. (2012) · The EMBO Reports · doi:10.1038/embor.2012.14 · Cited by 711 · see citing works
Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes
Galluzzi, L., Aaronson, S. A., Abrams, J., Alnemri, E. S., Andrews, D. W., Baehrecke, E. H., Bazan, N. G., Blagosklonny, M. V., Blomgren, K., Borner, C., et al. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.44 · Cited by 698 · see citing works
Suzuki, Y., Nakabayashi, Y., & Takahashi, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.161506698 · Cited by 654 · see citing works
RIP3 Induces Apoptosis Independent of Pronecrotic Kinase Activity
Mandal, P., Berger, S. B., Pillay, S., Moriwaki, K., Huang, C., Guo, H., Lich, J. D., Finger, J. N., Kasparcova, V., Votta, B. J., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.10.021 · Cited by 619 · see citing works
Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD
Mizumura, K., Cloonan, S. M., Nakahira, K., Bhashyam, A. R., Cervo, M., Kitada, T., Glass, K., Owen, C. A., Mahmood, A., Washko, G. R., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74985 · Cited by 611 · see citing works
The mitochondrial permeability transition initiates autophagy in rat hepatocytes
Elmore, S. P., Qian, T., Grissom, S. F., & Lemasters, J. J. (2001) · The FASEB Journal · doi:10.1096/fj.01-0206fje · Cited by 607 · see citing works
Molofsky, A. V., He, S., Bydon, M., Morrison, S. J., & Pardal, R. (2005) · Genes & Development · doi:10.1101/gad.1299505 · Cited by 586 · see citing works
Self-renewal as a therapeutic target in human colorectal cancer
Kreso, A., van Galen, P., Pedley, N. M., Lima-Fernandes, E., Frelin, C., Davis, T., Cao, L., Baiazitov, R., Du, W., Sydorenko, N., et al. (2014) · Nature Medicine · doi:10.1038/nm.3418 · Cited by 500 · see citing works
Bmi1 regulates mitochondrial function and the DNA damage response pathway
Liu, J., Cao, L., Chen, J., Song, S., Lee, I. H., Quijano, C., Liu, H., Keyvanfar, K., Chen, H., Cao, L.-Y., et al. (2009) · Nature · doi:10.1038/nature08040 · Cited by 474 · see citing works
XIAP inhibits caspase‐3 and ‐7 using two binding sites: evolutionarily conserved mechanism of IAPs
Scott, F. L., Denault, J., Riedl, S. J., Shin, H., Renatus, M., & Salvesen, G. S. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600544 · Cited by 420 · see citing works
Katayama, M., Kawaguchi, T., Berger, M. S., & Pieper, R. O. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402030 · Cited by 353 · see citing works
BMI1 Sustains Human Glioblastoma Multiforme Stem Cell Renewal
Abdouh, M., Facchino, S., Chatoo, W., Balasingam, V., Ferreira, J., & Bernier, G. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0968-09.2009 · Cited by 323 · see citing works
Bruggeman, S. W. M., Valk-Lingbeek, M. E., van der Stoop, P. P. M., Jacobs, J. J. L., Kieboom, K., Tanger, E., Hulsman, D., Leung, C., Arsenijevic, Y., Marino, S., et al. (2005) · Genes & Development · doi:10.1101/gad.1299305 · Cited by 315 · see citing works
Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis
Wu, X.-N., Yang, Z.-H., Wang, X.-K., Zhang, Y., Wan, H., Song, Y., Chen, X., Shao, J., & Han, J. (2014) · Cell Death & Differentiation · doi:10.1038/cdd.2014.77 · Cited by 299 · see citing works
MiR-15a and MiR-16 Control Bmi-1 Expression in Ovarian Cancer
Bhattacharya, R., Nicoloso, M. S., Arvizo, R. R., Wang, E., Cortez, A., Rossi, S., Calin, G. A., & Mukherjee, P. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-2552 · Cited by 240 · see citing works
Self-citationAmino acid signalling and the integration of metabolism
Meijer, A. J., & Dubbelhuis, P. F. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.07.012 · Cited by 215 · see citing works
Basit, F., Cristofanon, S., & Fulda, S. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2013.45 · Cited by 211 · see citing works
Selçuklu, S. D., Donoghue, M. T. A., Rehmet, K., Gomes, M. D. S., Fort, A., Kovvuru, P., Muniyappa, M. K., Kerin, M. J., Enright, A. J., & Spillane, C. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.335943 · Cited by 179 · see citing works
Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia
Kim, S. J., & Li, J. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.238 · Cited by 146 · see citing works
Bmi-1: At the crossroads of physiological and pathological biology
Bhattacharya, R., Mustafi, S. B., Street, M., Dey, A., & Dwivedi, S. K. D. (2015) · Genes & Diseases · doi:10.1016/j.gendis.2015.04.001 · Cited by 126 · see citing works
Self-citationMitochondrial Electron Transport Chain Complex III Is Required for Antimycin A to Inhibit Autophagy
Ma, X., Jin, M., Cai, Y. C., Xia, H., Long, K., Liu, J., Yu, Q., & Yuan, J. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.08.009 · Cited by 108 · see citing works
Zhang, J., Li, X., Mueller, M., Wang, Y., Zong, C., Deng, N., Vondriska, T. M., Liem, D. A., Yang, J., Kôrge, P., et al. (2008) · PROTEOMICS · doi:10.1002/pmic.200700851 · Cited by 100 · see citing works
Enhancing Chemotherapy Response with Bmi-1 Silencing in Ovarian Cancer
Wang, E., Bhattacharyya, S., Szabolcs, A., Rodriguez‐Aguayo, C., Jennings, N. B., Lopez‐Berestein, G., Mukherjee, P., Sood, A. K., & Bhattacharya, R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017918 · Cited by 82 · see citing works
Self-citationThe polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors
Bommi, P. V., Dimri, M., Sahasrabuddhe, A. A., Khandekar, J. D., & Dimri, G. P. (2010) · Cell Cycle · doi:10.4161/cc.9.13.12147 · Cited by 73 · see citing works
Mourgues, L., Imbert, V., Nebout, M., Colosetti, P., Neffati, Z., Lagadec, P., Verhoeyen, E., Peng, C., Duprez, E., Legros, L., et al. (2015) · Leukemia · doi:10.1038/leu.2015.112 · Cited by 60 · see citing works
Bmi1 promotes prostate tumorigenesis via inhibiting p16INK4A and p14ARF expression
Fan, C., He, L., Kapoor, A., Gillis, A., Rybak, A. P., Cutz, J., & Tang, D. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.08.009 · Cited by 59 · see citing works
Subkhankulova, T., Zhang, X., Leung, C., & Marino, S. (2010) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2010.06.006 · Cited by 48 · see citing works
Arrestin2 modulates androgen receptor activation
Purayil, H. T., Zhang, Y., Dey, A., et al. (2014) · Oncogene · doi:10.1038/onc.2014.252 · Cited by 21 · see citing works
Self-citationAutophagic cell death RIPs into tumors
Oberst, A. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.89 · Cited by 6 · see citing works
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Li, J., Song, P., Zhu, L., Aziz, N., Zhou, Q., Zhang, Y., Xu, W., Feng, L., Chen, D., Wang, X., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.16844 · Cited by 46 · see citing works
- Authors
- Dey, A., Mustafi, S. B., Saha, S., Kumar Dhar Dwivedi, S., Mukherjee, P., & Bhattacharya, R.
- Affiliations
- University of Oklahoma Medical Center (US)
- OU Health Stephenson Cancer Center (US)
- Corresponding author
- Bhattacharya, Resham
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2016-04-02
- Volume
- 12
- Issue
- 4
- Pages
- 659-670
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC4836029
- OpenAlex
- W2313960655
- Cited by
- 97
- References
- 60
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 17 · 2023: 12 · 2022: 14 · 2021: 15 · 2020: 7 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 2
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA157481, CA157481)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- BMI1, PTC-209, necroptosis, ovarian cancer, clonal growth, mitochondrial pathway, MLKL, chemoresistance, ATP depletion, cancer stem cells, non-apoptotic cell death
- MeSH terms
- Adenosine Triphosphate, Autophagy, Heterocyclic Compounds, 2-Ring, Humans, Mitochondria, Models, Biological, Necrosis, Thiazoles, Apoptosis, Caspases, Cell Line, Tumor, Polycomb Repressive Complex 1
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