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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.
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1 Ludwig-Maximilians-University, Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X); Chulalongkorn University, Department of Biochemistry and Microbiology/Pharmacognosy, Faculty of Pharmaceutical Sciences, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
2 Ludwig-Maximilians-University, Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X)
3 Ludwig-Maximilians-University, Department of Pharmacy, Center for Drug Research, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X)
4 Colorado State University, Department of Biochemistry and Molecular Biology, Fort Collins, USA (GRID:grid.47894.36) (ISNI:0000 0004 1936 8083)
5 Sapienza University of Rome, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Unit of Histology and Medical Embryology, Rome, Italy (GRID:grid.7841.a)
6 Yokohama University of Pharmacy, Yokohama, Japan (GRID:grid.443246.3) (ISNI:0000 0004 0619 079X)
7 Chulalongkorn University, Department of Biochemistry and Microbiology/Pharmacognosy, Faculty of Pharmaceutical Sciences, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)