The structural conformation of the tachykinin domain drives the anti‐tumoural activity of an octopus peptide in melanoma BRAFV600E. (29th July 2022)

• Record Type: Journal Article
• Authors: Moral‐Sanz, Javier; Fernandez‐Rojo, Manuel A.; Colmenarejo, Gonzalo; Kurdyukov, Sergey; Brust, Andreas; Ragnarsson, Lotten; Andersson, Åsa; Vila, Sabela F.; Cabezas‐Sainz, Pablo; Wilhelm, Patrick; Vela‐Sebastián, Ana; Fernández‐Carrasco, Isabel; Chin, Yanni K. Y.; López‐Mancheño, Yaiza; Smallwood, Taylor B.; Clark, Richard J.; Fry, Bryan G.; King, Glenn F.; Ramm, Grant A.; Alewood, Paul F.; Lewis, Richard J.; Mulvenna, Jason P.; Boyle, Glen M.; Sanchez, Laura E.; Neely, G. Gregory; Miles, John J.; Ikonomopoulou, Maria P.
• Is Part Of: British journal of pharmacology. Volume 179:Number 20(2022)
• Page Start: 4878
• Page End: 4896
• Publication Date: 2022-07-29
• Subjects: melanoma -- metabolism -- mitochondria -- ROS -- tachykinin‐receptors; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15923
• Languages: English
• ISSNs: 0007-1188

Abstract

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.