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3. Apoptotic stress causes mtDNA release during senescence and drives the SASP

Author

Victorelli, Stella, Salmonowicz, Hanna, Chapman, James, Martini, Helene, Vizioli, Maria Grazia, Riley, Joel S., Cloix, Catherine, Hall-Younger, Ella, Machado Espindola-Netto, Jair, Jurk, Diana, Lagnado, Anthony B., Sales Gomez, Lilian, Farr, Joshua N., Saul, Dominik, Reed, Rebecca, Kelly, George, Eppard, Madeline, Greaves, Laura C., Dou, Zhixun, Pirius, Nicholas, Szczepanowska, Karolina, Porritt, Rebecca A., Huang, Huijie, Huang, Timothy Y., Mann, Derek A., Masuda, Claudio Akio, Khosla, Sundeep, Dai, Haiming, Kaufmann, Scott H., Zacharioudakis, Emmanouil, Gavathiotis, Evripidis, LeBrasseur, Nathan K., Lei, Xue, Sainz, Alva G., Korolchuk, Viktor I., Adams, Peter D., Shadel, Gerald S., Tait, Stephen W. G., and Passos, João F.

Published
2023
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4. Author Correction: Apoptotic stress causes mtDNA release during senescence and drives the SASP

Author

Victorelli, Stella, Salmonowicz, Hanna, Chapman, James, Martini, Helene, Vizioli, Maria Grazia, Riley, Joel S., Cloix, Catherine, Hall-Younger, Ella, Machado Espindola-Netto, Jair, Jurk, Diana, Lagnado, Anthony B., Sales Gomez, Lilian, Farr, Joshua N., Saul, Dominik, Reed, Rebecca, Kelly, George, Eppard, Madeline, Greaves, Laura C., Dou, Zhixun, Pirius, Nicholas, Szczepanowska, Karolina, Porritt, Rebecca A., Huang, Huijie, Huang, Timothy Y., Mann, Derek A., Masuda, Claudio Akio, Khosla, Sundeep, Dai, Haiming, Kaufmann, Scott H., Zacharioudakis, Emmanouil, Gavathiotis, Evripidis, LeBrasseur, Nathan K., Lei, Xue, Sainz, Alva G., Korolchuk, Viktor I., Adams, Peter D., Shadel, Gerald S., Tait, Stephen W. G., and Passos, João F.

Published
2024
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5. Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics

Author

Koessinger, Anna L., Cloix, Catherine, Koessinger, Dominik, Heiland, Dieter Henrik, Bock, Florian J., Strathdee, Karen, Kinch, Kevin, Martínez-Escardó, Laura, Paul, Nikki R., Nixon, Colin, Malviya, Gaurav, Jackson, Mark R., Campbell, Kirsteen J., Stevenson, Katrina, Davis, Sandeep, Elmasry, Yassmin, Ahmed, Asma, O’Prey, Jim, Ichim, Gabriel, Schnell, Oliver, Stewart, William, Blyth, Karen, Ryan, Kevin M., Chalmers, Anthony J., Norman, Jim C., and Tait, Stephen W. G.

Published
2022
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11. The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis

Author

Clarke, Cassie J., Berg, Tracy J., Birch, Joanna, Ennis, Darren, Mitchell, Louise, Cloix, Catherine, Campbell, Andrew, Sumpton, David, Nixon, Colin, Campbell, Kirsteen, Bridgeman, Victoria L., Vermeulen, Peter B., Foo, Shane, Kostaras, Eleftherios, Jones, J. Louise, Haywood, Linda, Pulleine, Ellie, Yin, Huabing, Strathdee, Douglas, Sansom, Owen, Blyth, Karen, McNeish, Iain, Zanivan, Sara, Reynolds, Andrew R., and Norman, Jim C.

Published
2016
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12. Apoptotic stress causes mtDNA release during senescence and drives the SASP

Author

Mann, Derek Austin, Victorelli, Stella; Salmonowicz, Hanna; Chapman, James; Martini, Helene; Vizioli, Maria Grazia; Riley, Joel S.; Cloix, Catherine; Hall-Younger, Ella; Machado Espindola-Netto, Jair; Jurk, Diana; Lagnado, Anthony B.; Sales Gomez, Lilian; Farr, Joshua N.; Saul, Dominik; Reed, Rebecca; Kelly, George; Eppard, Madeline; Greaves, Laura C.; Dou, Zhixun; Pirius, Nicholas; Szczepanowska, Karolina; Porritt, Rebecca A.; Huang, Huijie; Huang, Timothy Y.; Masuda, Claudio Akio; Khosla, Sundeep; Dai, Haiming; Kaufmann, Scott H.; Zacharioudakis, Emmanouil; Gavathiotis, Evripidis; LeBrasseur, Nathan K.; Lei, Xue; Sainz, Alva G.; Korolchuk, Viktor I.; Adams, Peter D.; Shadel, Gerald S.; Tait, Stephen W. G.; Passos, João F., School of Medicine, Mann, Derek Austin, Victorelli, Stella; Salmonowicz, Hanna; Chapman, James; Martini, Helene; Vizioli, Maria Grazia; Riley, Joel S.; Cloix, Catherine; Hall-Younger, Ella; Machado Espindola-Netto, Jair; Jurk, Diana; Lagnado, Anthony B.; Sales Gomez, Lilian; Farr, Joshua N.; Saul, Dominik; Reed, Rebecca; Kelly, George; Eppard, Madeline; Greaves, Laura C.; Dou, Zhixun; Pirius, Nicholas; Szczepanowska, Karolina; Porritt, Rebecca A.; Huang, Huijie; Huang, Timothy Y.; Masuda, Claudio Akio; Khosla, Sundeep; Dai, Haiming; Kaufmann, Scott H.; Zacharioudakis, Emmanouil; Gavathiotis, Evripidis; LeBrasseur, Nathan K.; Lei, Xue; Sainz, Alva G.; Korolchuk, Viktor I.; Adams, Peter D.; Shadel, Gerald S.; Tait, Stephen W. G.; Passos, João F., and School of Medicine

Abstract

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS–STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan., This work was funded by NIH grants R01AG068048 (to J.F.P.), UG3CA268103 (to J.F.P.), P01 AG062413 (to S.K., J.N.F., N.K.L. and J.F.P.), P01 AG073084 and R01 AR069876 (to G.S.S.), F31 AG062099 (to A.G.S.), R01 AG068182-01 (to D.J.), R01 CA225996 (to S.H.K. and H.D.), R01 DK128552 (to J.N.F.), R01 AG071861-01 (to X.L. and P.D.A.), P01 AG073084 (to P.D.A. and X.L.), R01 AG076515 (to S.K.), U54 AG079754 (to S.K.), R01 AG061875 and RF1 AG070391 (to T.Y.H.), R01AG071861 (to P.D.A.) and R33AG61456-4 and R01AG064165; Department of Defense grant W81XWH-20-1-0792 (to E.G.); U54 AG79754 (to S.K. and N.K.L.); Cancer Research UK grants C40872/A2014, DRCNPG-Jun22\100011 (to S.W.G.T.); the Ted Nash Long Life Foundation (to J.F.P. and D.J.); The Glenn Foundation For Medical Research (to J.F.P. and N.K.L.); Hevolution/AFAR (to D.J.); a Robert and Arlene Kogod Center on Aging Career Development Award (to S.V.); a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (Capes)—Finance Code 001 and by the Universidade Federal do Rio de Janeiro (to C.A.M.); Cancer Research UK grant DRCPFA-Nov22/100001 and Wellcome grant 203105/Z/16/Z0 to L.C.G., BBSRC PhD studentship BB/R506345/1 (to G.K. and V.I.K.); UKRI cross-council Newcastle University Centre for Ageing and Vitality Ph.D. studentship MR/L016354/1 (to J.C.) and CRUK Awards C18342/A23390 and DRCRPG-Nov22/100007 and MRC MR/R023026/1 (to D.A.M.). G.S.S. holds the Audrey Geisel Chair in Biomedical Science. MS interactome analysis was performed at the Proteomic Core Facility of IMol Polish Academy of Sciences and supported by ReMedy International Research Agenda (Foundation of Polish Science, MAB/2017/2) and EMBO Installation Grant 5040-2022 (to K.S.). scRNA-seq was performed by the Sanford Burnham Prebys Genomics Core. G.S.S. holds the Audrey Geisel Chair in Biomedical Science and is supported by P30AG068635 as director of the San Diego Nathan Shock Center. We thank G. Nelson and the members of the Newcastle U

Published
2023

16. Sub-lethal apoptotic stress enables mtDNA release during senescence and drives the SASP

Author

Passos, Joao, primary, Chapman, James, additional, Salmonowicz, Hanna, additional, Victorelli, Stella, additional, Martini, Helene, additional, Riley, Joel, additional, Cloix, Catherine, additional, Shadel, Gerald, additional, Netto, Jair Machado Espindola, additional, Jurk, Diana, additional, Lagnado, Anthony, additional, Gomez, Lilian, additional, Farr, Joshua, additional, Saul, Dominik, additional, Reed, Becca, additional, Greaves, Laura, additional, Mann, Derek, additional, Masuda, Claudio Akio, additional, Khosla, Sundeep, additional, Dai, Haiming, additional, LeBrasseur, Nathan, additional, Korolchuk, Viktor, additional, Shae, Xue, additional, Adams, Peter, additional, Tait, Stephen, additional, Vizioli, Maria Grazia, additional, Castillo, Alva Sainz, additional, Kaufmann, Scott, additional, and Dou, Zhixun, additional

Published
2022
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20. Increased apoptotic priming of glioblastoma enables therapeutic targeting by BH3-mimetics

Author

Koessinger, Anna L, primary, Koessinger, Dominik, additional, Kinch, Kevin, additional, Martínez-Escardó, Laura, additional, Paul, Nikki R, additional, Elmasry, Yassmin, additional, Malviya, Gaurav, additional, Cloix, Catherine, additional, Campbell, Kirsteen J, additional, Bock, Florian J, additional, O’Prey, Jim, additional, Stevenson, Katrina, additional, Nixon, Colin, additional, Jackson, Mark R, additional, Ichim, Gabriel, additional, Stewart, William, additional, Blyth, Karen, additional, Ryan, Kevin M, additional, Chalmers, Anthony J, additional, Norman, Jim C, additional, and Tait, Stephen WG, additional

Published
2021
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21. A UV-B-specific signaling component orchestrates plant UV protection

Author

Brown, Bobby A., Cloix, Catherine, Jhiang, Guang Huai, Kaiserli, Eirini, Herzyk, Pawel, Kliebenstein, Daniel J., and Jenkins, Gareth I.

Subjects
Ultraviolet radiation -- Observations, Pathogenic microorganisms -- Research, Science and technology
Abstract

UV-B radiation in sunlight has diverse effects on humans, animals, plants, and microorganisms. UV-B can cause damage to molecules and cells, and consequently organisms need to protect against and repair UV damage to survive in sunlight. In plants, low non damaging levels of UV-B stimulate transcription of genes involved in UV-protective responses. However, remarkably little is known about the underlying mechanisms of UV-B perception and signal transduction. Here we report that Arabist's UV RESISTANCE LOCUS 8 (UVR8) is a UV-B-specific signaling component that orchestrates expression of a range of genes with vital UV-protective functions. Moreover, we show that UVR8 regulates expression of the transcription factor HY5 specifically when the plant is exposed to UV-B. We demonstrate that HY5 is a key effector of the UVR8 pathway, and that it is required for survival under UV-B radiation. UVR8 has sequence similarity to the neurotically guanine nucleotide exchange factor RCC1, but we found that it has little exchange activity. However, UVR8, like RCC1, is located principally in the nucleus and associates with chromatin via hi stones. Chromatin precipitation's showed that UVR8 associates with chromatin in the HY5 promoter region, providing a mechanistic basis for its involvement in regulating transcription. We conclude that UVR8 defines a UV-B-specific signaling pathway in plants that orchestrates the protective gene expression responses to UV-B required for plant survival in sunlight. pathogenesis's | ultraviolet-B radiation | UV RESISTANCE LOCUS 8

Published
2005

25. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency

Author

Giampazolias, Evangelos, Zunino, Barbara, Dhayade, Sandeep, Bock, Florian, Cloix, Catherine, Cao, Kai, Roca, Alba, Lopez, Jonathan, Ichim, Gabriel, Proïcs, Emma, Rubio-Patiño, Camila, Fort, Loic, Yatim, Nader, Woodham, Emma, Orozco, Susana, Taraborrelli, Lucia, Peltzer, Nieves, Lecis, Daniele, Machesky, Laura, Walczak, Henning, Albert, Matthew L., Milling, Simon, Oberst, Andrew, Ricci, Jean-Ehrland, Ryan, Kevin M., Blyth, Karen, and Tait, Stephen W.G.

Abstract

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.

Published
2017

26. Mitochondrial inner membrane permeabilisation enables mt DNA release during apoptosis

Author

Riley, Joel S, primary, Quarato, Giovanni, additional, Cloix, Catherine, additional, Lopez, Jonathan, additional, O'Prey, Jim, additional, Pearson, Matthew, additional, Chapman, James, additional, Sesaki, Hiromi, additional, Carlin, Leo M, additional, Passos, João F, additional, Wheeler, Ann P, additional, Oberst, Andrew, additional, Ryan, Kevin M, additional, and Tait, Stephen WG, additional

Published
2018
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27. Functional characterisation of Arabidopsis phototropin 1 in the hypocotyl apex

Author

Sullivan, Stuart, Takemiya, Atsushi, Kharshiing, Eros, Cloix, Catherine, Shimazaki, Ken-ichiro, and Christie, John M.

Subjects
fungi, food and beverages
Abstract

Phototropin (phot1) is a blue light-activated plasma membrane-associated kinase that acts as the principal photoreceptor for shoot phototropism in Arabidopsis in conjunction with the signalling component Non-Phototropic Hypocotyl 3 (NPH3). PHOT1 is uniformly expressed throughout the Arabidopsis hypocotyl, yet decapitation experiments have localised the site of light perception to the upper hypocotyl. This prompted us to investigate in more detail the functional role of the hypocotyl apex, and the regions surrounding it, in establishing phototropism. We used a non-invasive approach where PHOT1-GFP (P1-GFP) expression was targeted to the hypocotyl apex of the phot-deficient mutant using the promoters of CUP-SHAPED COTYLEDON 3 (CUC3) and AINTEGUMENTA (ANT). Expression of CUC3::P1-GFP was clearly visible at the hypocotyl apex, with weaker expression in the cotyledons, whereas ANT::P1-GFP was specifically targeted to the developing leaves. Both lines showed impaired curvature to 0.005 μmol m-2 s-1 unilateral blue light, indicating that regions below the apical meristem are necessary for phototropism. Curvature was however apparent at higher fluence rates. Moreover, CUC3::P1-GFP partially or fully complemented petiole positioning, leaf flattening and chloroplast accumulation, but not stomatal opening. Yet, tissue analysis of NPH3 de-phosphorylation showed that CUC3::P1-GFP and ANT::P1-GFP mis-express very low levels of phot1 that likely account for this responsiveness. Our spatial targeting approach therefore excludes the hypocotyl apex as the site for light perception for phototropism and shows that phot1-mediated NPH3 de-phosphorylation is tissue autonomous and occurs more prominently in the basal hypocotyl.

Published
2016

28. Dimer/monomer status and in vivo function of salt-bridge mutants of the plant UV-B photoreceptor UVR8

Author

Heilmann, Monika, Velanis, Christos N., Cloix, Catherine, Smith, Brian O., Christie, John M., and Jenkins, Gareth I.

Abstract

UV RESISTANCE LOCUS8 (UVR8) is a photoreceptor for ultraviolet-B (UV-B) light that initiates photomorphogenic responses in plants. UV-B photoreception causes rapid dissociation of dimeric UVR8 into monomers that interact with CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1) to initiate signal transduction. Experiments with purified UVR8 show that the dimer is maintained by salt-bridge interactions between specific charged amino acids across the dimer interface. However, little is known about the importance of these charged amino acids in determining dimer/monomer status and UVR8 function in plants. Here we evaluate the use of different methods to examine dimer/monomer status of UVR8 and show that mutations of several salt-bridge amino acids affect dimer/monomer status, interaction with COP1 and photoreceptor function of UVR8 in vivo. In particular, the salt-bridges formed between arginine 286 and aspartates 96 and 107 are key to dimer formation. Mutation of arginine 286 to alanine impairs dimer formation, interaction with COP1 and function in vivo, whereas mutation to lysine gives a weakened dimer that is functional in vivo, indicating the importance of the positive charge of the arginine/lysine residue for dimer formation. Notably, a UVR8 mutant in which aspartates 96 and 107 are conservatively mutated to asparagine is strongly impaired in dimer formation but mediates UV-B responses in vivo with a similar dose-response relationship to wild-type. The UV-B responsiveness of this mutant does not correlate with dimer formation and monomerisation, indicating that monomeric UVR8 has the potential for UV-B photoreception, initiating signal transduction and responses in plants.

Published
2016

30. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity

Author

Hernandez-Fernaud, Juan R., primary, Ruengeler, Elena, additional, Casazza, Andrea, additional, Neilson, Lisa J., additional, Pulleine, Ellie, additional, Santi, Alice, additional, Ismail, Shehab, additional, Lilla, Sergio, additional, Dhayade, Sandeep, additional, MacPherson, Iain R., additional, McNeish, Iain, additional, Ennis, Darren, additional, Ali, Hala, additional, Kugeratski, Fernanda G., additional, Al Khamici, Heba, additional, van den Biggelaar, Maartje, additional, van den Berghe, Peter V.E., additional, Cloix, Catherine, additional, McDonald, Laura, additional, Millan, David, additional, Hoyle, Aoisha, additional, Kuchnio, Anna, additional, Carmeliet, Peter, additional, Valenzuela, Stella M., additional, Blyth, Karen, additional, Yin, Huabing, additional, Mazzone, Massimiliano, additional, Norman, Jim C., additional, and Zanivan, Sara, additional

Published
2017
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31. Analysis of the 5S RNA pool in Arabodopsis thaliana: RNAs are heterogeneous and only two of the genomic 5S loci produce mature 5S RNA

Author

Cloix, Catherine, Tutois, Sylvie, Yukawa, Yasushi, Mathieu, Olivier, and Cuvillier, Claudine; Espagnol, Marie-Claude; Picard, Georges; Tourmente, Sylvette

Subjects
Genetic transcription -- Research, Chromosomes -- Research, RNA -- Research, Genetic research, Health
Abstract

One major 5S RNA was revealed by an analysis of mature 5S RNA from tissues, developmental stages, and polysomes in Arabidopsis thaliana. Both major and minor 5S transcripts come from only two of the genomic 5S loci: chromosome 4 and chromosome 5 major block.

Published
2002

33. Evolutionary conservation of structure and function of the UVR8 photoreceptor from the liverwort Marchantia polymorpha and the moss Physcomitrella patens.

Author

Soriano, Gonzalo, Cloix, Catherine, Heilmann, Monika, Núñez‐Olivera, Encarnación, Martínez‐Abaigar, Javier, and Jenkins, Gareth I.

Subjects
*PLANT photoreceptors, *MARCHANTIA polymorpha, *PHYSCOMITRELLA patens, *ARABIDOPSIS, *GENE expression
Abstract

The ultraviolet-B ( UV-B) photoreceptor UV RESISTANCE LOCUS 8 ( UVR8) mediates photomorphogenic responses to UV-B in Arabidopsis through differential gene expression, but little is known about UVR8 in other species. Bryophyte lineages were the earliest diverging embryophytes, thus being the first plants facing the UV-B regime typical of land. We therefore examined whether liverwort and moss species have functional UVR8 proteins and whether they are regulated similarly to Arabidopsis UVR8., We examined the expression, dimer/monomer status, cellular localisation and function of Marchantia polymorpha and Physcomitrella patens UVR8 in experiments with bryophyte tissue and expression of green fluorescent protein ( GFP)- UVR8 fusions in Nicotiana leaves and transgenic Arabidopsis., P. patens expresses two UVR8 genes that encode functional proteins, whereas the single M. polymorpha UVR8 gene expresses two transcripts by alternative splicing that encode functional UVR8 variants. P. patens UVR8 proteins form dimers that monomerise and accumulate in the nucleus following UV-B exposure, similar to Arabidopsis UVR8, but M. polymorpha UVR8 has weaker dimers and the proteins appear more constitutively nuclear., We conclude that liverwort and moss species produce functional UVR8 proteins. Although there are differences in expression and regulation of P. patens and M. polymorpha UVR8, the mechanism of UVR8 action is strongly conserved in evolution. [ABSTRACT FROM AUTHOR]

Published
2018
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34. Analysis of 5S rDNA Loci among Arabidopsis Ecotypes and Subspecies

Author

Tutois, S., Cloix, Catherine, Mathieu, Olivier, Cuvillier, Claudine, Tourmente, Sylvette, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), The Beatson Institute for Cancer Research, University of Glasgow, Université Blaise Pascal - Clermont-Ferrand 2 (UBP), TUTOIS, Sylvie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV] Life Sciences [q-bio], [SDV.GEN.GPL]Life Sciences [q-bio]/Genetics/Plants genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GPL] Life Sciences [q-bio]/Genetics/Plants genetics, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2002

37. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency.

Author

Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proïcs E, Rubio-Patiño C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H, Albert ML, Milling S, Oberst A, Ricci JE, Ryan KM, Blyth K, and Tait SWG

Subjects
Aniline Compounds pharmacology, Animals, Antineoplastic Agents pharmacology, Apoptosis, Colonic Neoplasms drug therapy, Colonic Neoplasms immunology, Colonic Neoplasms pathology, Genotype, HeLa Cells, Humans, Inhibitor of Apoptosis Proteins metabolism, Macrophage Activation, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mitochondria drug effects, Mitochondria immunology, Mitochondria pathology, Mitochondrial Membranes drug effects, Mitochondrial Membranes immunology, Mitochondrial Membranes pathology, NF-kappa B deficiency, Necrosis, Permeability, Phenotype, Protein Serine-Threonine Kinases metabolism, RNA Interference, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I metabolism, Signal Transduction, Sulfonamides pharmacology, Time Factors, Transfection, Tumor Necrosis Factor-alpha metabolism, NF-kappaB-Inducing Kinase, Caspases metabolism, Colonic Neoplasms enzymology, Inflammation Mediators metabolism, Mitochondria enzymology, Mitochondrial Membranes enzymology, NF-kappa B metabolism
Abstract

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.

Published
2017
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