The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62

Linares, Juan F.; Cid-Diaz, Tania; Durán, Abraham Madroñal; Osrodek, Marta; Martínez-Ordóñez, Anxo; Reina-Campos, Miguel; Kuo, Hui-Hsuan; Elemento, Olivier; Martín, Miguel; Cordes, Thekla; Thompson, Timothy C.; Metallo, Christian M.; Moscat, Jorge; Diaz‐Meco, María T.

doi:10.1016/j.celrep.2022.110792

Cited by 34 publications

(30 citation statements)

References 57 publications

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“…Another orthogonal method to increase NAD + bioavailability may be the inhibition of NAD + consumption [ 46 ]. Thus, we incubated LST platelets with olaparib, a clinically approved inhibitor of the major NAD + consuming enzyme PARP1 [ 47 ]. The inhibition of PARP1 by 20 μM olaparib successfully increased the NAD + /NADH ratio ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of mitochondrial complex I leading to NAD+/NADH imbalance in type 2 diabetic patients who developed late stent thrombosis: Evidence from an integrative analysis of platelet bioenergetics and metabolomics

Gao

Cui²,

Liu³

et al. 2022

Redox Biology

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Section: Resultsmentioning

confidence: 99%

Inhibition of mitochondrial complex I leading to NAD+/NADH imbalance in type 2 diabetic patients who developed late stent thrombosis: Evidence from an integrative analysis of platelet bioenergetics and metabolomics

Gao

Cui²,

Liu³

et al. 2022

Redox Biology

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“…Additionally, despite any oxygen conditions, tumor‐derived lactate promotes the formation of blood vessels by inducing hypoxia‐inducible factor 1α (HIF‐1α)‐mediated VEGF expression in cancer cells, and the expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor receptor 2 (VEGFR‐2) in neighboring endothelial cells (Sonveaux et al, 2012). Except for the lactate‐avid cells, lactate can also feed other types of cells in the TME, such as cancer‐associated fibroblasts and Treg cells (Linares et al, 2022; Watson et al, 2021).…”

Section: The Role Of Lactate Under Pathological Conditionsmentioning

confidence: 99%

Lactate: a pearl dropped in the ocean—an overlooked signal molecule in physiology and pathology

Liu

et al. 2022

Cell Biology International

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Lactate, once recognized as a wasty product from anaerobic glycolysis, is proved to be a pivotal signal molecule. Lactate accumulation occurs in diverse physiological and pathological settings due to the imbalance between lactate production and clearance. Under the condition with drastic changes in local microenvironment, such as tumorigenesis, inflammation, and microbial infection, the glycolysis turns to be active in surrounding cells leading to increased lactate release. Meanwhile, lactate can be utilized by these cells as an energy substrate and acts as a signal molecule to regulate cell functions through receptor‐dependent or independent pathways. In this review, we tended to tease out the contribution of lactate in tumor progression and immunomodulation. And we also discussed the accessory role of lactate, beyond as the energy source only, in the growth of invading pathogens.

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“…Recent studies demonstrate that normal fibroblasts can differentiate into CAFs as protective responses to stresses under tumor microenvironment via the p62-Nrf2-pathway [ 252 ]. Furthermore, a molecular mechanism for CAFs activation has shown that tumor secreted lactate downregulates p62 in the stroma blocking AP-1-mediated p62 transcription [ 253 ]. Interestingly, we have described changes in the expression of Gαq affecting some partners such as p62 promoting its downregulation and favoring autophagic flux [ 21 ].…”

Section: Autophagy In Disease For Good and For Bad: Gαq Involvementmentioning

confidence: 99%

Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

et al. 2022

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All processes in human physiology relies on homeostatic mechanisms which require the activation of specific control circuits to adapt the changes imposed by external stimuli. One of the critical modulators of homeostatic balance is autophagy, a catabolic process that is responsible of the destruction of long-lived proteins and organelles through a lysosome degradative pathway. Identification of the mechanism underlying autophagic flux is considered of great importance as both protective and detrimental functions are linked with deregulated autophagy. At the mechanistic and regulatory levels, autophagy is activated in response to diverse stress conditions (food deprivation, hyperthermia and hypoxia), even a novel perspective highlight the potential role of physical forces in autophagy modulation. To understand the crosstalk between all these controlling mechanisms could give us new clues about the specific contribution of autophagy in a wide range of diseases including vascular disorders, inflammation and cancer. Of note, any homeostatic control critically depends in at least two additional and poorly studied interdependent components: a receptor and its downstream effectors. Addressing the selective receptors involved in autophagy regulation is an open question and represents a new area of research in this field. G-protein coupled receptors (GPCRs) represent one of the largest and druggable targets membrane receptor protein superfamily. By exerting their action through G proteins, GPCRs play fundamental roles in the control of cellular homeostasis. Novel studies have shown Gαq, a subunit of heterotrimeric G proteins, as a core modulator of mTORC1 and autophagy, suggesting a fundamental contribution of Gαq-coupled GPCRs mechanisms in the control of this homeostatic feedback loop. To address how GPCR-G proteins machinery integrates the response to different stresses including oxidative conditions and mechanical stimuli, could provide deeper insight into new signaling pathways and open potential and novel therapeutic strategies in the modulation of different pathological conditions.

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The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62

Cited by 34 publications

References 57 publications

Inhibition of mitochondrial complex I leading to NAD+/NADH imbalance in type 2 diabetic patients who developed late stent thrombosis: Evidence from an integrative analysis of platelet bioenergetics and metabolomics

Inhibition of mitochondrial complex I leading to NAD+/NADH imbalance in type 2 diabetic patients who developed late stent thrombosis: Evidence from an integrative analysis of platelet bioenergetics and metabolomics

Lactate: a pearl dropped in the ocean—an overlooked signal molecule in physiology and pathology

Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

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