1. The structural conformation of the tachykinin domain drives the anti-tumoural activity of an octopus peptide in melanoma BRAF V600E .
- Author
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Moral-Sanz J, Fernandez-Rojo MA, Colmenarejo G, Kurdyukov S, Brust A, Ragnarsson L, Andersson Å, Vila SF, Cabezas-Sainz P, Wilhelm P, Vela-Sebastián A, Fernández-Carrasco I, Chin YKY, López-Mancheño Y, Smallwood TB, Clark RJ, Fry BG, King GF, Ramm GA, Alewood PF, Lewis RJ, Mulvenna JP, Boyle GM, Sanchez LE, Neely GG, Miles JJ, and Ikonomopoulou MP
- Subjects
- Adenosine Triphosphate, Animals, Calcium, Cell Line, Tumor, Humans, Mice, Mutation, Octopodiformes chemistry, Peptides pharmacology, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf therapeutic use, RNA, Messenger, Reactive Oxygen Species, Tachykinins genetics, Tachykinins therapeutic use, Zebrafish genetics, Antineoplastic Agents pharmacology, Melanoma drug therapy, Melanoma pathology
- Abstract
Background and Purpose: Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma., Experimental Approach: We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish)., Key Results: Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAF
V600E -mutated cells with minimal effects on fibroblasts. In melanoma-treated cells, Octpep-1 increased ROS with unaltered mitochondrial membrane potential and promoted non-mitochondrial and mitochondrial respiration with inefficient ATP coupling. Molecular modelling revealed that the cytotoxicity of Octpep-1 depends upon the α-helix and polyproline conformation in the C-terminal region of the peptide. A truncated form of the C-terminal end of Octpep-1 displayed enhanced potency and efficacy against melanoma. Octpep-1 reduced the progression of tumours in xenograft melanoma mice and zebrafish., Conclusion and Implications: We unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma., (© 2022 British Pharmacological Society.)- Published
- 2022
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