Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2.
Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2.
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DOI：
10.1038/s41598-021-88196-6
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发表时间：
2021-04-19
影响因子：
4.6
通讯作者：
Grimm C
中科院分区：
文献类型：
--
作者：
Netcharoensirisuk P;Abrahamian C;Tang R;Chen CC;Rosato AS;Beyers W;Chao YK;Filippini A;Di Pietro S;Bartel K;Biel M;Vollmar AM;Umehara K;De-Eknamkul W;Grimm C
双孔通道2 （TPC2）存在于内溶酶体膜中，也存在于溶酶体相关细胞器中，如产生黑色素的黑素体。hTPC2的功能获得多态性与黑色素生成减少和金发有关。反之亦然，基因消融TPC2会增加黑色素的产生。由于TPC2在内溶酶体和黑素小体中的双重活性，我们在这里展示了黑色素生成与黑色素瘤增殖、迁移和侵袭之间的负相关。我们的研究结果得到了TPC2基因消融和药理抑制的支持。从机制上讲，我们的数据显示TPC2的丢失/阻断导致MITF蛋白水平降低，MITF是黑色素瘤进展的主要调节因子，但黑色素生成酶酪氨酸酶的活性增加。因此，TPC2抑制通过干扰酪氨酸酶活性，增加黑色素小体中紫外线阻断黑色素的合成，并通过增加gsk3 β介导的MITF降解来减少MITF驱动的黑色素瘤进展，从而在黑色素瘤预防和治疗方面提供了双重益处。
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.
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影响因子：
8.6
作者：
Chen, Cheng-Chang;Butz, Elisabeth S.;Grimm, Christian
通讯作者：
Grimm, Christian
DOI：
10.1073/pnas.1705739114
发表时间：
2017-10-10
影响因子：
11.1
作者：
Chao, Yu-Kai;Schludi, Verena;Grimm, Christian
通讯作者：
Grimm, Christian
DOI：
10.1073/pnas.1406029111
发表时间：
2014-11-04
影响因子：
11.1
作者：
Favia, Annarita;Desideri, Marianna;Filippini, Antonio
通讯作者：
Filippini, Antonio
影响因子：
0.7
作者：
Parrington, John;Lear, Pamela;Hachem, Alaa
通讯作者：
Hachem, Alaa
影响因子：
4.6
作者：
Pafumi I;Festa M;Papacci F;Lagostena L;Giunta C;Gutla V;Cornara L;Favia A;Palombi F;Gambale F;Filippini A;Carpaneto A
通讯作者：
Carpaneto A