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Mitochondrial permeabilization engages NF-?B-dependent anti-tumour activity under caspase deficiency.

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-?B 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-?B, 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.

SUBMITTER: Giampazolias E

PROVIDER: S-EPMC5624512 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Giampazolias Evangelos E Zunino Barbara B Dhayade Sandeep S Bock Florian F Cloix Catherine C Cao Kai K Roca Alba A Lopez Jonathan J Ichim Gabriel G Proïcs Emma E Rubio-Patiño Camila C Fort Loic L Yatim Nader N Woodham Emma E Orozco Susana S Taraborrelli Lucia L Peltzer Nieves N Lecis Daniele D Machesky Laura L Walczak Henning H Albert Matthew L ML Milling Simon S Oberst Andrew A Ricci Jean-Ehrland JE Ryan Kevin M KM Blyth Karen K Tait Stephen W G SWG

Nature cell biology 20170828 9

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 ...[more]

PMID: 28846096

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Project description:Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined 'high inflammation' individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying 'high inflammation' compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

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Mitochondrial permeabilization engages NF-?B-dependent anti-tumour activity under caspase deficiency.

Publications

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

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