Melanosome maturation proteins Oca2, Mitfa and Vps11 are differentially required for cisplatin resistance in zebrafish melanocytes.

Abstract

Melanoma is the deadliest form of skin cancer, partially due to its inherent resistance to therapy. Here, we test in live larvae the hypothesis that mature melanosomes contribute to resistance to chemotherapeutic drug, cisplatin, via drug sequestration. We also compare three melanosome biogenesis proteins-microphthalmia-associated transcription factor (Mitfa), vacuolar protein sorting 11 (Vps11) and oculocutaneous albinism 2 (Oca2) to determine their respective contributions to chemoresistance. Melanocytes in zebrafish larvae harbouring loss-of-function mutations in the mitfa, vps11 or oca2 genes are more sensitive to cisplatin damage than wild-type larvae. As a comparison, we examined sensory hair cells of the lateral line, which are sensitive to cisplatin. Hair cells in oca2 and mitfa mutants do not show increased cisplatin sensitivity when compared to wild-type larvae, suggesting the increase in cisplatin sensitivity could be melanocyte specific. However, hair cells in vps11 mutants are more sensitive to cisplatin than their wild-type counterparts, suggesting that this mutation increases cisplatin susceptibility in multiple cell types. This is the first in vivo study to show an increase in chemotherapeutic drug sensitivity when melanosome maturation mutations are present. The proteins tested, especially Oca2, represent novel drug targets for increasing the efficiency of melanoma chemotherapy treatment.

• Authors: Kersten A Peterson, Samantha Neuffer, Miranda E Bean, Leslie New, Allison B Coffin, Cynthia D Cooper
• Journal: Experimental dermatology (Exp Dermatol) Vol. 28 Issue 7 Pg. 795-800 (07 2019) ISSN: 1600-0625 [Electronic] Denmark
• PMID: 30977151 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Membrane Transport Proteins
• Microphthalmia-Associated Transcription Factor
• OCA2 protein, zebrafish
• Vesicular Transport Proteins
• Zebrafish Proteins
• mitfa protein, zebrafish
• vacuolar protein sorting 11, zebrafish
• Cisplatin

Topics

• Animals
• Cisplatin (pharmacology)
• Disease Models, Animal
• Drug Resistance, Neoplasm
• In Situ Hybridization
• Melanocytes (cytology)
• Melanosomes (physiology)
• Membrane Transport Proteins (physiology)
• Microphthalmia-Associated Transcription Factor (physiology)
• Mutation
• Vesicular Transport Proteins (physiology)
• Zebrafish
• Zebrafish Proteins (physiology)