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Targeting Electron Transport Chain Confers Therapeutic Vulnerability in Castration-Resistant Prostate Cancer

ABSTRACT: Targeting Electron Transport Chain Confers Therapeutic Vulnerability in Castration-Resistant Prostate Cancer

PROVIDER: PRJNA853056 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19854954_1.fastq.gz	Fastqsanger.gz
	SRR19854954_2.fastq.gz	Fastqsanger.gz
	SRR19854955_1.fastq.gz	Fastqsanger.gz
	SRR19854955_2.fastq.gz	Fastqsanger.gz
	SRR19854956_1.fastq.gz	Fastqsanger.gz

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Targeting Electron Transport Chain Confers Therapeutic Vulnerability in Castration-Resistant Prostate Cancer

Project description:Most prostate cancer will develop into castration-resistant prostate cancer, which is the most frequent cause of death for prostate cancer patients. Despite novel androgen receptor antagonists have significantly improved clinical outcomes for these patients, some patients still could not benefit from existing treatment regimens. By analyzing the single-cell RNA-sequencing data and bulk-sequencing data, we discovered that oxidative phosphorylation and electron transport chain (ETC) pathway were enhanced in the prostate cancer microenvironment following tumor progression. Meanwhile, high ETC was related to poor clinical outcomes in prostate cancer patients. Both in vitro and in vivo castration-resistant prostate cancer models demonstrated that ETC inhibitor marked suppressed tumor growth and the synergistic antitumor efficacy of the combination of ETC inhibitor and androgen receptor antagonist. Our study indicates that ETC activity is a metabolic vulnerability for advanced prostate cancer and can serve as a novel therapeutic target.

2023-01-15 | GSE206962 | GEO

Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

Project description:Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of Complex I (CI) and II (CII), the gatekeepers for initiating electron flow, remains unclear. Here, we report that loss of CII, but not CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex I-antigen processing and presentation (MHC-APP) genes that is independent of interferon signaling. Furthermore, knock-out of MCJ, to promote electron entry preferentially via CI, provides proof-of-concept of ETC rewiring to achieve anti-tumor responses without side effects associated with an overall reduction in mitochondrial respiration in non-cancer cells. Our results hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

Project description:Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

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Effect of mitochondrial electron transport chain blockade on transcriptomic profile in human H460 cells

Project description:Cancer cells reprogram their metabolism to support cell growth and proliferation in harsh environments. To assess how human cells respond to defective mitochondrial respiration, we analyzed metabolomics profiles in cells with deficient electron transport chain (ETC). We found that ETC deficiency induces an accumulation of purine nucleotides. Additionally, we revealed that ETC blockade suppressed de novo purine nucleotide biosynthesis while enhanced purine salvage. This metabolic rewiring of purine nucleotide biosynthesis is not regulated at the transcriptional level. Instead, stable isotope tracing experiments showed that ETC blockade promoted the oxidative branch of pentose phosphate pathway to elevate phosphoribosyl diphosphate to drive purine salvage. In summary, our findings delineate how cells remodel purine metabolism in response to ETC blockade, and uncover a new metabolic vulnerability in tumors with low respiration.

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Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Project description:Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

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Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Project description:The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of NLRP3 inflammasome through multiple mechanisms including generation of mitochondrial ROS. Here we report that mitochondrial electron transport chain (ETC) complexes I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase (AOX), which can respectively complement the functional loss of mitochondrial complex I or III, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP but a ROS independent mechanism.

2022-03-09 | GSE197606 | GEO

Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [bulk RNA-seq]

Project description:Loss of antigen presentation by MHCI is a common mechanism of tumor immune evasion. Mitochondrial oxidative phosphorylation (OXPHOS) capacity influences MHCI expression, but the underlying molecular mechanisms remain unclear. Here, we demonstrate that the relative flow of electrons through complex I or II of the mitochondrial electron transport chain (ETC) regulates MHCI expression and antigen presentation in cancer cells. Specifically, reducing electron flow from complex II increases mitochondrial succinate which activates transcription of MHCI and antigen processing and presentation (APP) genes. These phenotypes are independent of the interferon (IFN) signaling pathway and driven by succinate-mediated enzymatic inhibition of lysine-specific demethylases, KDM5A/B and destabilization of polycomb repressor complex 2 (PRC2). Finally, knockout of the mitochondrial Complex I inhibitor protein, MCJ, preferentially reduces electron flow through Complex II and increases succinate which drives an enhanced antigen-dependent CD8+ T cell response to mouse melanoma tumors in vivo. These findings suggest that the mitochondrial ETC can be manipulated therapeutically to enhance antitumor immune responses independently of IFNγ.

2022-12-31 | GSE198346 | GEO

Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity

Project description:Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity

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Genes expressed in age-induced mitochondrial DNA deletion mutation containing / Electron Transport abnormal cells

Project description:Muscle tissue was longitudinally characterized histologically for electron transport function by staining 1mm of quadriceps muscle at 70 micron intervals for the activities of two complexes in the mitochondrial electron transport chain, Cytochrome C Oxidase and Succinate Dehydrogenase. Unstained serial cryosections were prepared for Laser Capture Microdissection. Target cells from the serial sections were isolated and pooled for RNA extraction, amplification and hybridization on Affymetrix microarrays. We selected homogeneous populations of muscle fibers for expression profiling based upon the presence/absence of electron transport dysfunction caused by the somatic accumulation of mitochondrial DNA deletion mutations.

2013-03-01 | GSE35607 | GEO

Phosphoglycerate dehydrogenase causes electron transport chain defect via impaired heme synthesis: RNA sequencing.

Project description:Phosphoglycerate dehydrogenase causes electron transport chain defect via impaired heme synthesis: RNA sequencing.

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