Oncogenic Gq/11 signaling acutely drives and chronically sustains metabolic reprogramming in uveal melanoma

Onken, Michael D.; Noda, Sarah E.; Kaltenbronn, Kevin M.; Frankfater, Cheryl; Makepeace, Carol M.; Fettig, Nikki; Piggott, Kisha; Custer, Philip L.; Ippolito, Joseph E.; Blumer, Kendall J.

doi:10.1016/j.jbc.2021.101495

Cited by 9 publications

(21 citation statements)

References 64 publications

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“…Our data further highlights that targeting this process in UM may enhance treatment efficacy and indicates the potential use of CysLT 1 antagonists to inhibit OXPHOS in a combinatorial treatment approach with alternative immune or traditional targeted therapies. UM does not exhibit a classical Warburg effect ( 84 ). Onken et al ( 84 ) report that that oncogenic G q/11 signaling in UM cell lines promotes both glycolytic activity and mitochondrial respiration ( 84 ).…”

Section: Discussionmentioning

confidence: 99%

“…UM does not exhibit a classical Warburg effect ( 84 ). Onken et al ( 84 ) report that that oncogenic G q/11 signaling in UM cell lines promotes both glycolytic activity and mitochondrial respiration ( 84 ). Additionally, metabolic heterogeneity in BAP1 mutant vs. BAP1 wild-type UM was recently described based on oxidative phosphorylation gene expression profiles ( 85 ).…”

Section: Discussionmentioning

confidence: 99%

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1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

Slater

Bosch²,

Smith³

et al. 2023

Front. Med.

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Uveal melanoma (UM) is an intraocular cancer with propensity for liver metastases. The median overall survival (OS) for metastatic UM (MUM) is 1.07 years, with a reported range of 0.84–1.34. In primary UM, high cysteinyl leukotriene receptor 1 (CysLT1) expression associates with poor outcomes. CysLT1 antagonists, quininib and 1,4-dihydroxy quininib, alter cancer hallmarks of primary and metastatic UM cell lines in vitro. Here, the clinical relevance of CysLT receptors and therapeutic potential of quininib analogs is elaborated in UM using preclinical in vivo orthotopic xenograft models and ex vivo patient samples. Immunohistochemical staining of an independent cohort (n = 64) of primary UM patients confirmed high CysLT1 expression significantly associates with death from metastatic disease (p = 0.02; HR 2.28; 95% CI 1.08–4.78), solidifying the disease relevance of CysLT1 in UM. In primary UM samples (n = 11) cultured as ex vivo explants, 1,4-dihydroxy quininib significantly alters the secretion of IL-13, IL-2, and TNF-α. In an orthotopic, cell line-derived xenograft model of MUM, 1,4-dihydroxy quininib administered intraperitoneally at 25 mg/kg significantly decreases ATP5B expression (p = 0.03), a marker of oxidative phosphorylation. In UM, high ATP5F1B is a poor prognostic indicator, whereas low ATP5F1B, in combination with disomy 3, correlates with an absence of metastatic disease in the TCGA-UM dataset. These preclinical data highlight the diagnostic potential of CysLT1 and ATP5F1B in UM, and the therapeutic potential of 1,4-dihydroxy quininib with ATP5F1B as a companion diagnostic to treat MUM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

Slater

Bosch²,

Smith³

et al. 2023

Front. Med.

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“…The potential and reported connections of Gαq signaling that we have described with this axis [ 21 ] may provide new insights in the mechanisms underlying these metabolic alterations. Recent studies have further confirmed the relevance of Gαq signaling for driving metabolic reprogramming in uveal melanoma [ 211 ] and in the regulation of glucose and lipid homeostasis [ 212 ] reinforcing a critical role of GPCR-Gαq system in metabolic diseases. Further investigation will be required to define the mechanisms involved.…”

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

confidence: 96%

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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“…Inhibition of mitogenic Gα q/11 signaling by application of FR to models expressing Gα q Q209L/P mutants has been demonstrated in several instances. Treatment with FR resulted in reduced tumor growth in mouse xenografts, , reduced glucose uptake in uveal melanoma cells in vitro and in vivo, and decreased colony formation of uveal melanoma cells in 3D cell culture . As these effects cannot be attributed to the GDI properties of FR, inhibitor binding was hypothesized to switch the nucleotide preference of Gα q Q209L/P from GTP to GDP in an allosteric fashion .…”

Section: Molecular Mechanism Of Gαq Protein Inhibition By Ym and Frmentioning

confidence: 99%

Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate Gα_q/11-Mediated Signaling Pathways

Voss

2023

ACS Pharmacol. Transl. Sci.

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The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are natural products, which inhibit heterotrimeric Gαq/11 proteins with high potency and outstanding selectivity. Historically, pharmacological modulation of Gα proteins was only achieved by treatment with pertussis toxin and cholera toxin, whose application can be tedious and is restricted to the inhibition of Gαi/o proteins and activation of Gαs proteins, respectively. The breakthrough discovery and characterization of YM and FR rendered the closely related Gαq, Gα11, and Gα14 proteins amenable to pharmacological inhibition, and since then, both compounds have become widely used in molecular pharmacology and were also proven to be efficacious in animal models of disease. In the past years, both YM and FR were thoroughly characterized and have substantially contributed to an improved understanding of Gαq/11 signaling on a molecular and cellular level. Yet, the possibilities to interrogate Gαq/11 signaling in complex systems have only been exploited in a very limited number of studies, whose promising initial results warrant further application of YM and FR in basic and translational research. As both compounds have become commercially available as of late, this review focuses on their application in cell-based assays and in vivo systems, highlighting their qualities as tool compounds and providing instructions for their use.

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Oncogenic Gq/11 signaling acutely drives and chronically sustains metabolic reprogramming in uveal melanoma

Cited by 9 publications

References 64 publications

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate Gα_q/11-Mediated Signaling Pathways

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Oncogenic Gq/11 signaling acutely drives and chronically sustains metabolic reprogramming in uveal melanoma

Cited by 9 publications

References 64 publications

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate Gαq/11-Mediated Signaling Pathways

Contact Info

Product

Resources

About

Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate Gα_q/11-Mediated Signaling Pathways