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1.
Mol Oncol ; 18(5): 1054-1057, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38520041

RESUMO

Mitochondrial metabolism and electron transport chain (ETC) function are essential for tumour proliferation and metastasis. However, the impact of ETC function on cancer immunogenicity is not well understood. In a recent study, Mangalhara et al. found that inhibition of complex II leads to enhanced tumour immunogenicity, T-cell-mediated cytotoxicity and inhibition of tumour growth. Surprisingly, this antitumour effect is mediated by succinate accumulation affecting histone methylation. Histone methylation promotes the transcriptional upregulation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes in a manner independent of interferon signalling. Modulating mitochondrial electron flow to enhance tumour immunogenicity provides an exciting new therapeutic avenue and may be particularly attractive for tumours with reduced expression of MHC-APP genes or dampened interferon signalling.


Assuntos
Mitocôndrias , Neoplasias , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/metabolismo , Animais , Transporte de Elétrons
2.
Sci Adv ; 10(11): eadk7329, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489367

RESUMO

Small interfering RNAs (siRNAs) are widely used in biomedical research and in clinical trials. Here, we demonstrate that siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown. Genetically targeting mitochondrial antiviral-signaling protein (MAVS) reversed the siRNA-mediated sensitizing effect, but no activation of canonical MAVS signaling, which involves phosphorylation of IkBα and interferon regulatory transcription factor 3 (IRF3), was observed. In contrast, MAVS mediated a noncanonical signal resulting in a prominent increase in mitochondrial ROS levels, and increase in the BACH1/pNRF2 transcription factor ratio and GPX4 up-regulation, which was associated with a 50% decrease in intracellular glutathione levels. We conclude that siRNAs commonly sensitize to ferroptosis and may severely compromise the conclusions drawn from silencing approaches in biomedical research. Finally, as ferroptosis contributes to a variety of pathophysiological processes, we cannot exclude side effects in human siRNA-based therapeutical concepts that should be clinically tested.


Assuntos
Ferroptose , Transdução de Sinais , Humanos , RNA Interferente Pequeno/genética , Ferroptose/genética , Regulação para Cima , Fatores de Transcrição/metabolismo
3.
J Transl Med ; 22(1): 317, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38549077

RESUMO

The anti-apoptotic BCL-2 protein family regulates cancer cell survival, thus it represents an important therapeutic target. Indeed, a drug class, called BH3-mimetics, have been developed to directly target BCL2 proteins and promote cancer cell death. Conventional wisdom suggests that the primary anti-cancer effect of BCL-2 inhibition is through induction of cancer cell death. However, a recent study by Zhao and colleagues describes that BCL-2 inhibition also enhances the function of classical dendritic cells, unleashing their role in immunosurveillance, promoting T cell immunity and tumour regression. Thus, inhibiting anti-apoptotic BCL-2 function may have a multi-pronged anti-tumour action.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/farmacologia , Proteínas Reguladoras de Apoptose/uso terapêutico , Linhagem Celular Tumoral
6.
Trends Cell Biol ; 34(3): 225-238, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37573235

RESUMO

Cytotoxic chemo-, radio-, and targeted therapies frequently elicit apoptotic cancer cell death. Mitochondrial outer membrane permeabilization (MOMP) is a critical, regulated step in this apoptotic pathway. The residual cancer cells that survive treatment serve as the seeds of eventual relapse and are often functionally characterized by their transient tolerance of multiple therapeutic treatments. New studies suggest that, in these cells, a sublethal degree of MOMP, reflective of incomplete apoptotic commitment, is widely observed. Here, we review recent evidence that this sublethal MOMP drives the aggressive features of residual cancer cells while templating a host of unique vulnerabilities, highlighting how failed apoptosis may counterintuitively enable new therapeutic strategies to target residual disease (RD).


Assuntos
Mitocôndrias , Membranas Mitocondriais , Humanos , Membranas Mitocondriais/metabolismo , Mitocôndrias/metabolismo , Neoplasia Residual/metabolismo , Apoptose/fisiologia
7.
Nature ; 622(7983): 627-636, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37821702

RESUMO

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.


Assuntos
Apoptose , Senescência Celular , Citosol , DNA Mitocondrial , Mitocôndrias , Animais , Camundongos , Citosol/metabolismo , DNA Mitocondrial/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria , Estudo de Prova de Conceito , Inflamação/metabolismo , Fenótipo , Longevidade , Envelhecimento Saudável
8.
Cell Death Dis ; 14(9): 600, 2023 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-37684238

RESUMO

Intracellular Ca2+ signals control several physiological and pathophysiological processes. The main tool to chelate intracellular Ca2+ is intracellular BAPTA (BAPTAi), usually introduced into cells as a membrane-permeant acetoxymethyl ester (BAPTA-AM). Previously, we demonstrated that BAPTAi enhanced apoptosis induced by venetoclax, a BCL-2 antagonist, in diffuse large B-cell lymphoma (DLBCL). This finding implied a novel interplay between intracellular Ca2+ signaling and anti-apoptotic BCL-2 function. Hence, we set out to identify the underlying mechanisms by which BAPTAi enhances cell death in B-cell cancers. In this study, we discovered that BAPTAi alone induced apoptosis in hematological cancer cell lines that were highly sensitive to S63845, an MCL-1 antagonist. BAPTAi provoked a rapid decline in MCL-1-protein levels by inhibiting mTORC1-driven Mcl-1 translation. These events were not a consequence of cell death, as BAX/BAK-deficient cancer cells exhibited similar downregulation of mTORC1 activity and MCL-1-protein levels. Next, we investigated how BAPTAi diminished mTORC1 activity and identified its ability to impair glycolysis by directly inhibiting 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) activity, a previously unknown effect of BAPTAi. Notably, these effects were also induced by a BAPTAi analog with low affinity for Ca2+. Consequently, our findings uncover PFKFB3 inhibition as an Ca2+-independent mechanism through which BAPTAi impairs cellular metabolism and ultimately compromises the survival of MCL-1-dependent cancer cells. These findings hold two important implications. Firstly, the direct inhibition of PFKFB3 emerges as a key regulator of mTORC1 activity and a promising target in MCL-1-dependent cancers. Secondly, cellular effects caused by BAPTAi are not necessarily related to Ca2+ signaling. Our data support the need for a reassessment of the role of Ca2+ in cellular processes when findings were based on the use of BAPTAi.


Assuntos
Neoplasias , Monoéster Fosfórico Hidrolases , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Ácido Egtázico , Fosfofrutoquinase-2/genética
9.
Biochem Soc Trans ; 51(1): 457-472, 2023 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-36815695

RESUMO

Cytosolic DNA is recognized by the innate immune system as a potential threat. During apoptotic cell death, mitochondrial DNA (mtDNA) release activates the DNA sensor cyclic GMP-AMP synthase (cGAS) to promote a pro-inflammatory type I interferon response. Inflammation following mtDNA release during apoptotic cell death can be exploited to engage anti-tumor immunity and represents a potential avenue for cancer therapy. Additionally, various studies have described leakage of mtDNA, independent of cell death, with different underlying cues such as pathogenic infections, changes in mtDNA packaging, mtDNA stress or reduced mitochondrial clearance. The interferon response in these scenarios can be beneficial but also potentially disadvantageous, as suggested by a variety of disease phenotypes. In this review, we discuss mechanisms underlying mtDNA release governed by cell death pathways and summarize release mechanisms independent of cell death. We further highlight the similarities and differences in mtDNA release pathways, outlining gaps in our knowledge and questions for further research. Together, a deeper understanding of how and when mtDNA is released may enable the development of drugs to specifically target or inhibit mtDNA release in different disease settings.


Assuntos
DNA Mitocondrial , Mitocôndrias , Humanos , DNA Mitocondrial/metabolismo , Mitocôndrias/metabolismo , Inflamação/metabolismo , Apoptose , Interferons/metabolismo
10.
Cell Death Differ ; 30(2): 304-312, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36447047

RESUMO

Mitochondria have recently emerged as key drivers of inflammation associated with cell death. Many of the pro-inflammatory pathways activated during cell death occur upon mitochondrial outer membrane permeabilization (MOMP), the pivotal commitment point to cell death during mitochondrial apoptosis. Permeabilised mitochondria trigger inflammation, in part, through the release of mitochondrial-derived damage-associated molecular patterns (DAMPs). Caspases, while dispensable for cell death during mitochondrial apoptosis, inhibit activation of pro-inflammatory pathways after MOMP. Some of these mitochondrial-activated inflammatory pathways can be traced back to the bacterial ancestry of mitochondria. For instance, mtDNA and bacterial DNA are highly similar thereby activating similar cell autonomous immune signalling pathways. The bacterial origin of mitochondria suggests that inflammatory pathways found in cytosol-invading bacteria may be relevant to mitochondrial-driven inflammation after MOMP. In this review, we discuss how mitochondria can initiate inflammation during cell death highlighting parallels with bacterial activation of inflammation. Moreover, we discuss the roles of mitochondrial inflammation during cell death and how these processes may potentially be harnessed therapeutically, for instance to improve cancer treatment.


Assuntos
Mitocôndrias , Membranas Mitocondriais , Humanos , Membranas Mitocondriais/metabolismo , Mitocôndrias/metabolismo , Morte Celular , Apoptose/fisiologia , Inflamação/metabolismo
11.
Nat Rev Immunol ; 23(3): 159-173, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35879417

RESUMO

Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.


Assuntos
Mitocôndrias , Neoplasias , Humanos , Mitocôndrias/metabolismo , Inflamação/patologia , Alarminas , Neoplasias/patologia
12.
Dev Cell ; 57(24): 2679-2682, 2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36538893

RESUMO

In this selection, we celebrate the art of science by highlighting some of the submitted cover images from the past year. In this collection, our authors share the stories behind their inspiration for how to portray their science to captivate a broader audience.

13.
Cell ; 185(18): 3356-3374.e22, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36055199

RESUMO

Drug-tolerant persister cells (persisters) evade apoptosis upon targeted and conventional cancer therapies and represent a major non-genetic barrier to effective cancer treatment. Here, we show that cells that survive treatment with pro-apoptotic BH3 mimetics display a persister phenotype that includes colonization and metastasis in vivo and increased sensitivity toward ferroptosis by GPX4 inhibition. We found that sublethal mitochondrial outer membrane permeabilization (MOMP) and holocytochrome c release are key requirements for the generation of the persister phenotype. The generation of persisters is independent of apoptosome formation and caspase activation, but instead, cytosolic cytochrome c induces the activation of heme-regulated inhibitor (HRI) kinase and engagement of the integrated stress response (ISR) with the consequent synthesis of ATF4, all of which are required for the persister phenotype. Our results reveal that sublethal cytochrome c release couples sublethal MOMP to caspase-independent initiation of an ATF4-dependent, drug-tolerant persister phenotype.


Assuntos
Citocromos c , Neoplasias/tratamento farmacológico , Animais , Apoptose , Proteínas de Transporte , Caspases/metabolismo , Citocromos c/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Camundongos , Mitocôndrias/metabolismo
14.
Nat Commun ; 13(1): 3775, 2022 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-35798717

RESUMO

Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.


Assuntos
GTP Fosfo-Hidrolases , Mitocôndrias , GTP Fosfo-Hidrolases/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Transdução de Sinais
15.
J Cell Biol ; 221(6)2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35575773

RESUMO

Many types of regulated cell death exist, however the non-cell autonomous effects of specific forms of cell death remain poorly understood. Addressing this, Shkarina et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202109038) describe an optogenetic method to activate distinct modes of cell death in select cells.

16.
Dev Cell ; 57(10): 1211-1225.e6, 2022 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-35447090

RESUMO

Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.


Assuntos
Caspases , Dinâmica Mitocondrial , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Caspases/metabolismo , Dano ao DNA , Instabilidade Genômica , Humanos , Proteína X Associada a bcl-2/metabolismo
17.
Cell Death Differ ; 29(10): 2089-2104, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35473984

RESUMO

Glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. We investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti-apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non-malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti-apoptotic BCL-2 family members. High anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein-targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3-mimetics.


Assuntos
Glioblastoma , Adulto , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína bcl-X
18.
Elife ; 112022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35256052

RESUMO

Mechanical stress is known to fuel several hallmarks of cancer, ranging from genome instability to uncontrolled proliferation or invasion. Cancer cells are constantly challenged by mechanical stresses not only in the primary tumour but also during metastasis. However, this latter has seldom been studied with regards to mechanobiology, in particular resistance to anoikis, a cell death programme triggered by loss of cell adhesion. Here, we show in vitro that migrating breast cancer cells develop resistance to anoikis following their passage through microporous membranes mimicking confined migration (CM), a mechanical constriction that cancer cells encounter during metastasis. This CM-induced resistance was mediated by Inhibitory of Apoptosis Proteins, and sensitivity to anoikis could be restored after their inhibition using second mitochondria-derived activator of caspase (SMAC) mimetics. Anoikis-resistant mechanically stressed cancer cells displayed enhanced cell motility and evasion from natural killer cell-mediated immune surveillance, as well as a marked advantage to form lung metastatic lesions in mice. Our findings reveal that CM increases the metastatic potential of breast cancer cells.


Assuntos
Anoikis , Neoplasias da Mama , Animais , Anoikis/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Feminino , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais
19.
Nat Commun ; 12(1): 6572, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34772930

RESUMO

Damaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair.


Assuntos
Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima/efeitos dos fármacos , Cicatrização
20.
Eur J Immunol ; 51(12): 3228-3238, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34633664

RESUMO

The use of bacteria as an alternative cancer therapy has been reinvestigated in recent years. SL7207: an auxotrophic Salmonella enterica serovar Typhimurium aroA mutant with immune-stimulatory potential has proven a promising strain for this purpose. Here, we show that systemic administration of SL7207 induces melanoma tumor growth arrest in vivo, with greater survival of the SL7207-treated group compared to control PBS-treated mice. Administration of SL7207 is accompanied by a change in the immune phenotype of the tumor-infiltrating cells toward pro-inflammatory, with expression of the TH 1 cytokines IFN-γ, TNF-α, and IL-12 significantly increased. Interestingly, Ly6C+ MHCII+ monocytes were recruited to the tumors following SL7207 treatment and were pro-inflammatory. Accordingly, the abrogation of these infiltrating monocytes using clodronate liposomes prevented SL7207-induced tumor growth inhibition. These data demonstrate a previously unappreciated role for infiltrating inflammatory monocytes underlying bacterial-mediated tumor growth inhibition. This information highlights a possible novel role for monocytes in controlling tumor growth, contributing to our understanding of the immune responses required for successful immunotherapy of cancer.


Assuntos
Imunoterapia , Melanoma Experimental , Monócitos/imunologia , Salmonella typhimurium/imunologia , Células Th1/imunologia , Animais , Citocinas/imunologia , Feminino , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Salmonella typhimurium/genética
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