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.
Highlights
Wile many cancer incidences are falling, the incidence rate of malignant melanoma is rising at a rate of 3–7% in most European countries versus 2.6% in the US, and is expected to further rise
Ambrosio et al (2016) have recently shown that knockout of two-pore channel Two-pore channel 2 (TPC2) in human MNT-1 melanoma cells elicits a strong increase in pigment content and that this effect can be reversed by transient overexpression of TPC2-GFP4
We found that melanoma cell proliferation, migration, and invasion are inversely correlated with TPC2-dependent melanin production as loss of TPC2 increases melanin content but decreases proliferation/migration/invasion
Summary
Wile many cancer incidences are falling, the incidence rate of malignant melanoma is rising at a rate of 3–7% in most European countries versus 2.6% in the US, and is expected to further rise. We found that melanoma cell proliferation, migration, and invasion are inversely correlated with TPC2-dependent melanin production as loss of TPC2 increases melanin content but decreases proliferation/migration/invasion. This is possible due to independent mechanisms: via regulation of MITF (microphthalmia-associated transcription factor) protein levels through interference with endolysosomal activity of TPC2 and endolysosomal GSK3β degradation on the one hand and on the other hand via MITF-independent regulation of tyrosinase activity by TPC2 in melanosomes. Flavonoids, previously proposed anti-cancer agents emerge as direct inhibitors of TPC2 and the higher risk for blond haired individuals or individuals with light pigmentation to develop melanoma may be directly correlated to TPC2 activity and GOF variation
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