Measurement of Melanin Metabolism in Live Cells by [U-13C]-L-Tyrosine Fate Tracing Using Liquid Chromatography-Mass Spectrometry

Chen, Qiuying; Zhou, Dong; Abdel‐Malek, Zalfa; Zhang, Fengli; Goff, Philip S.; Sviderskaya, Elena V.; Wakamatsu, Kazumasa; Ito, Shosuke; Gross, Steven S.; Zippin, Jonathan H.

doi:10.1016/j.jid.2021.01.007

Cited by 15 publications

(16 citation statements)

References 72 publications

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“…29 Tyrosine is first converted into L-dihydroxyphenylalanine (DOPA) via tyrosinase, and this is the rate limiting step in melanin synthesis. 23,30 Consistent with the premise that tyrosinase activity increases in parallel with eumelanin content across the human pigment spectrum 6,31 , we detected approximately 300% more DOPA in cultures of primary human DMCs, as compared to LMCs (Figure 2b).…”

Section: Dopa Inhibits MC Proliferation and Melanoma In Vitro And In Vivosupporting

confidence: 83%

CHRM1 is a Druggable Melanoma Target Whose Endogenous Activity is Determined by Inherited Genetic Variation in DOPA Production

Doepner

Natale

Lee

et al. 2021

Preprint

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Melanoma risk is higher for people with lightly pigmented skin (1:38) compared to those with darkly pigmented skin (1:1000). While this difference is typically attributed to the ultraviolet radiation (UVR) shielding effect of melanin pigment, here we show that other cell-intrinsic differences between dark and light MCs, independent of melanin and UV, regulate MC proliferative capacity, cellular differentiation state, and susceptibility to malignant transformation. These differences are driven by dihydroxyphenylalanine (DOPA), a melanin synthesis intermediate, and result from DOPA antagonism of the muscarinic acetylcholine receptor M1 (CHRM1), a G Protein-Coupled Receptor (GPCR) expressed in MCs, but not previously known to bind DOPA, nor to affect melanoma pathobiology. Pharmacologic CHRM1 antagonism in melanoma leads to downregulation of c-Myc and FOXM1, both of which are proliferation drivers associated with aggressive melanoma. In preclinical melanoma models, pharmacologic CHRM1 inhibition in vivo inhibited melanoma growth. CHRM1 may be a new therapeutic target for melanoma.

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Section: Dopa Inhibits MC Proliferation and Melanoma In Vitro And In Vivosupporting

confidence: 83%

CHRM1 is a Druggable Melanoma Target Whose Endogenous Activity is Determined by Inherited Genetic Variation in DOPA Production

Doepner

Natale

Lee

et al. 2021

Preprint

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“…Tyrosine is first converted into l -DOPA via Tyr, and this is the rate-limiting step in melanin synthesis ( 26 , 30 ). Consistent with the premise that Tyr activity increases in parallel with eumelanin content across the human pigment spectrum ( 6 , 31 ), we detected approximately 300% more DOPA in cultures of primary human DMCs, as compared to LMCs (Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling

et al. 2022

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Melanoma risk is 30 times higher in people with lightly pigmented skin versus darkly pigmented skin. Using primary human melanocytes representing the full human skin pigment continuum and preclinical melanoma models, we show that cell-intrinsic differences between dark and light melanocytes regulate melanocyte proliferative capacity and susceptibility to malignant transformation, independent of melanin and ultraviolet exposure. These differences result from dihydroxyphenylalanine (DOPA), a melanin precursor synthesized at higher levels in melanocytes from darkly pigmented skin. We used both high-throughput pharmacologic and genetic in vivo CRISPR screens to determine that DOPA limits melanocyte and melanoma cell proliferation by inhibiting the muscarinic acetylcholine receptor M 1 (CHRM1) signaling. Pharmacologic CHRM1 antagonism in melanoma leads to depletion of c-Myc and FOXM1, both of which are proliferation drivers associated with aggressive melanoma. In preclinical mouse melanoma models, pharmacologic inhibition of CHRM1 or FOXM1 inhibited tumor growth. CHRM1 and FOXM1 may be new therapeutic targets for melanoma.

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“…Metabolite changes have been detected so far in various physiological processes involving the skin, including melanogenesis, aging, and even death [ 32 , 64 , 77 ].…”

Section: Resultsmentioning

confidence: 99%

Current Knowledge in Skin Metabolomics: Updates from Literature Review

Paganelli

Righi

Tarentini³

et al. 2022

IJMS

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Metabolomic profiling is an emerging field consisting of the measurement of metabolites in a biological system. Since metabolites can vary in relation to different stimuli, specific metabolic patterns can be closely related to a pathological process. In the dermatological setting, skin metabolomics can provide useful biomarkers for the diagnosis, prognosis, and therapy of cutaneous disorders. The main goal of the present review is to present a comprehensive overview of the published studies in skin metabolomics. A search for journal articles focused on skin metabolomics was conducted on the MEDLINE, EMBASE, Cochrane, and Scopus electronic databases. Only research articles with electronically available English full text were taken into consideration. Studies specifically focused on cutaneous microbiomes were also excluded from the present search. A total of 97 papers matched all the research criteria and were therefore considered for the present work. Most of the publications were focused on inflammatory dermatoses and immune-mediated cutaneous disorders. Skin oncology also turned out to be a relevant field in metabolomic research. Only a few papers were focused on infectious diseases and rarer genetic disorders. All the major metabolomic alterations published so far in the dermatological setting are described extensively in this review.

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Measurement of Melanin Metabolism in Live Cells by [U-13C]-L-Tyrosine Fate Tracing Using Liquid Chromatography-Mass Spectrometry

Cited by 15 publications

References 72 publications

CHRM1 is a Druggable Melanoma Target Whose Endogenous Activity is Determined by Inherited Genetic Variation in DOPA Production

CHRM1 is a Druggable Melanoma Target Whose Endogenous Activity is Determined by Inherited Genetic Variation in DOPA Production

Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling

Current Knowledge in Skin Metabolomics: Updates from Literature Review

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