PUBLICATION
The structural conformation of the tachykinin domain drives the anti-tumoral activity of an octopus peptide in melanoma BRAFV600E
- Authors
- Moral-Sanz, J., Fernandez-Rojo, M.A., Colmenarejo, G., Kurdyukov, S., Brust, A., Ragnarsson, L., Andersson, Å., Vila, S.F., Cabezas-Sainz, P., Wilhelm, P., Vela-Sebastian, A., Fernández-Carrasco, I., Chin, Y.K.Y., López-Mancheño, Y., Smallwood, T.B., Clark, R.J., Fry, B.G., King, G.F., Ramm, G.A., Alewood, P.F., Lewis, R.J., Mulvenna, J.P., Boyle, G.M., Sanchez, L.E., Neely, G.G., Miles, J.J., Ikonomopoulou, M.P.
- ID
- ZDB-PUB-220714-1
- Date
- 2022
- Source
- British journal of pharmacology 179(20): 4878-4896 (Journal)
- Registered Authors
- Cabezas-Sainz, Pablo
- Keywords
- Melanoma, ROS, metabolism, mitochondria, tachykinin-receptors
- MeSH Terms
-
- Adenosine Triphosphate
- Animals
- Antineoplastic Agents*/pharmacology
- Calcium
- Cell Line, Tumor
- Humans
- Melanoma*/drug therapy
- Melanoma*/pathology
- 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
- PubMed
- 35818835 Full text @ Br. J. Pharmacol.
Citation
Moral-Sanz, J., Fernandez-Rojo, M.A., Colmenarejo, G., Kurdyukov, S., Brust, A., Ragnarsson, L., Andersson, Å., Vila, S.F., Cabezas-Sainz, P., Wilhelm, P., Vela-Sebastian, A., Fernández-Carrasco, I., Chin, Y.K.Y., López-Mancheño, Y., Smallwood, T.B., Clark, R.J., Fry, B.G., King, G.F., Ramm, G.A., Alewood, P.F., Lewis, R.J., Mulvenna, J.P., Boyle, G.M., Sanchez, L.E., Neely, G.G., Miles, J.J., Ikonomopoulou, M.P. (2022) The structural conformation of the tachykinin domain drives the anti-tumoral activity of an octopus peptide in melanoma BRAFV600E. British journal of pharmacology. 179(20):4878-4896.
Abstract
Background and purpose Over the past decades, targeted therapies and immunotherapy have vastly 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 BRAFV600E -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. Despite similarities with tachykinin peptides, knock-out or pharmacological blockade of tachykinin receptors suggested that Octpep-1 acts via a tachykinin-independent mechanism. 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. Indeed, a truncated form of the C-terminal end of Octpep-1 displayed enhanced potency and efficacy against melanoma. Octpep-1 reduced the progression of tumors in xenograft melanoma mice and zebrafish, confirming its therapeutic potential in human BRAF-mutated melanoma.
Conclusion and implications We unravel the intrinsic anti-tumoral properties of a tachykinin peptide, possessing a pharmacology independent of tachykinin-receptors. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in-vitro and prevents tumor progression in-vivo, providing the foundation for a potential therapy against melanoma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping