Defueling the cancer: ATP synthase as an emerging target in cancer therapy

Wang, Ting; Ma, Fei; Qian, Haili

doi:10.1016/j.omto.2021.08.015

Cited by 46 publications

(34 citation statements)

References 149 publications

(182 reference statements)

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“…Next, we investigated whether Analog-1 modulated the energetic metabolism by evaluating its effect on the activity of ATP-synthase, which is required for malignant tumor growth and was recently proposed as an emerging target for cancer therapy [ 32 , 33 ]. For this purpose, we evaluated the ATP-synthase activity in SH-SY5Y and MZ2-MEL cell lines treated with 10 μM Analog-1 or vehicle alone (control) for 48 h by luminometric measurements.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we demonstrated that the energetic metabolism of tumor cells is also dramatically downregulated by Analog-1 through the inhibition of ATP-synthase activity, resulting in ATP reduction and AMP increase. ATP-synthase is a central enzyme of the cellular energy metabolism, which is highly expressed during cancer growth and linked to a poor prognosis in almost all tumors [ 32 , 52 , 53 , 54 , 55 ]. Targeting ATP-synthase has been proposed as a promising approach for cancer therapy [ 33 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

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Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Principi

Sondo

Bianchi

et al. 2022

Cancers

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RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro- or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F1Fo ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma- and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Principi

Sondo

Bianchi

et al. 2022

Cancers

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“…These results suggest that asteltoxin treatment at the low concentrations (1 μg/mL) that are sufficient for EV inhibition results in a decrease in ATP levels to some extent, but does not induce mitochondria damage, which would lead to apoptosis. Interestingly, oligomycin, a mitochondrial inhibitor which binds to F0-ATPase 26 , also caused a similar decrease in ATP levels as asteltoxin and reduced EV production (Supplementally Fig. S3 ).…”

Section: Resultsmentioning

confidence: 82%

“…1 A), which was previously identified as a mitochondrial inhibitor. The target of asteltoxin is recognized as F1 region of ATP synthase 26 , which was supported by the crystal structure of F1-ATPase complexed with aurovertin B 27 , which is a polyketide sharing a polyene α-pyrone-type structure of asteltoxin. Asteltoxin was identified using electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) and nuclear magnetic resonance (NMR) analyses, and these results were compared to authentic spectral data 28 .…”

Section: Resultsmentioning

confidence: 86%

Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function

Mitani

Lin

Sakamoto

et al. 2022

Sci Rep

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Cancer cells secrete aberrantly large amounts of extracellular vesicles (EVs) including exosomes, which originate from multivesicular bodies (MVBs). Because EVs potentially contribute to tumor progression, EV inhibitors are of interest as novel therapeutics. We screened a fungal natural product library. Using cancer cells engineered to secrete luciferase-labeled EVs, we identified asteltoxin, which inhibits mitochondrial ATP synthase, as an EV inhibitor. Low concentrations of asteltoxin inhibited EV secretion without inducing mitochondrial damage. Asteltoxin attenuated cellular ATP levels and induced AMPK-mediated mTORC1 inactivation. Consequently, MiT/TFE transcription factors are translocated into the nucleus, promoting transcription of lysosomal genes and lysosome activation. Electron microscopy analysis revealed that the number of lysosomes increased relative to that of MVBs and the level of EVs decreased after treatment with asteltoxin or rapamycin, an mTORC1 inhibitor. These findings suggest that asteltoxin represents a new type of EV inhibitor that controls MVB fate.

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“…Given the progression of the candidate drug J147, which targets ATP synthase, to clinical trial as a potential treatment for AD ( Goldberg, 2018 ), as well as the deeper consideration of the enzyme as a target in anti-cancer therapies ( Wang et al, 2021 ), a deeper understanding of the frequency, type, and location of the oxidative modifications of the mitochondrial ATP synthase enzyme should allow for the development of candidate drugs to treat these diseases in the future.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial ATP Synthase is a Target of Oxidative Stress in Neurodegenerative Diseases

Ebanks

Chakrabarti

2022

Front. Mol. Biosci.

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The mitochondrial ATP synthase is responsible for the production of cellular ATP, and it does so by harnessing the membrane potential of the mitochondria that is produced by the sequential oxidation of select cellular metabolites. Since the structural features of ATP synthase were first resolved nearly three decades ago, significant progress has been made in understanding its role in health and disease. Mitochondrial dysfunction is common to neurodegeneration, with elevated oxidative stress a hallmark of this dysfunction. The patterns of this oxidative stress, including molecular targets and the form of oxidative modification, can vary widely. In this mini review we discuss the oxidative modifications of ATP synthase that have been observed in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Oxidative modifications of ATP synthase in Alzheimer’s disease are well-documented, and there is a growing body of knowledge on the subject in Parkinson’s disease. The consideration of ATP synthase as a pharmacological target in a variety of diseases underlines the importance of understanding these modifications, both as a potential target, and also as inhibitors of any pharmacological intervention.

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Defueling the cancer: ATP synthase as an emerging target in cancer therapy

Cited by 46 publications

References 149 publications

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function

Mitochondrial ATP Synthase is a Target of Oxidative Stress in Neurodegenerative Diseases

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