Dataset Information

Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2.

ABSTRACT: Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2 increases melanin production. We show here an inverse correlation between melanin production and melanoma proliferation, migration, and invasion due to the dual activity of TPC2 in endolysosomes and melanosomes. Our results are supported by both genetic ablation and pharmacological inhibition of TPC2. Mechanistically, our data show that loss/block of TPC2 results in reduced protein levels of MITF, a major regulator of melanoma progression, but an increased activity of the melanin-generating enzyme tyrosinase. TPC2 inhibition thus provides a twofold benefit in melanoma prevention and treatment by increasing, through interference with tyrosinase activity, the synthesis of UV blocking melanin in melanosomes and by decreasing MITF-driven melanoma progression by increased GSK3β-mediated MITF degradation.

SUBMITTER: Netcharoensirisuk P

PROVIDER: S-EPMC8055690 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2.

Netcharoensirisuk Ponsawan P Abrahamian Carla C Tang Rachel R Chen Cheng-Chang CC Rosato Anna Scotto AS Beyers Wyatt W Chao Yu-Kai YK Filippini Antonio A Di Pietro Santiago S Bartel Karin K Biel Martin M Vollmar Angelika M AM Umehara Kaoru K De-Eknamkul Wanchai W Grimm Christian C

Scientific reports 20210419 1

Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2 increases melanin production. We show here an inverse correlation between melanin production and melanoma proliferation, migration, and invasion due to the dual activity of TPC2 in endolysosomes and melanosome ...[more]

PMID: 33875769

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Project description:Secondary sexual traits displayed by males and females may have evolved as a signal of individual quality. However, both individual quality and investment on producing or maintaining enhanced sexual traits change as individuals age. At the same time, the costs associated to produce sexual traits might be attenuated or increased if environmental conditions are benign or worse respectively. Accordingly, environmental conditions are expected to shape the association between the expression of sexual traits and their reproductive outcome as individuals age. Nonetheless, little is known about the environmental influence on the co-variation between sexual traits and reproductive outcome throughout the life of individuals. We studied the age-dependency of the number and size of back spots, a melanin-based and sexual trait in adults of common kestrels (Falco tinnunculus). We analysed the age-dependence of reproductive traits and the environmental influence, defined as vole abundance, using a 10-year individual-based dataset. We broke down age-related changes of reproductive traits into within- and between-individual variation to assess their contribution to population-level patterns. Our results showed a within-individual decrease in the number, but not the size, of back spots in males. The size of back spots was positively correlated with food availability in males. Reproductive performance of males increased as they aged, in agreement with the life-history theory but depending of vole abundance. Remarkably, we found that having fewer back spots was positively associated with clutch size only for old individuals under low-food conditions. We suggest that environmental variation may shape the association between the expression of a sexual signal and reproductive outcome. We speculate that the reliability of sexual traits is higher when environmental conditions are poor only for old individuals. Within an evolutionary context, we suggest that the expression of sexual traits might be constrained by environmental conditions at later stages of life.

Dataset Information

Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2.

Publications

Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2.

Similar Datasets

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