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Open AccessArticle

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

1
Translational Venomics Group, Madrid Institute for Advanced Studies in Food, E28049 Madrid, Spain
2
Hepatic Regenerative Medicine Group, Madrid Institute for Advanced Studies in Food, E28049 Madrid, Spain
3
Diamantina Institute, The University of Queensland, Brisbane, QLD 4072, Australia
4
Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
5
Infectious Diseases Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
6
AB SCIEX, 2 Gilda Court, Mulgrave, Melbourne, VIC 3170, Australia
7
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
8
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
9
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
10
School of Biological Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
11
Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
12
The Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Cairns, QLD 4811, Australia
13
Centre for Molecular Therapeutics, James Cook University, Cairns, QLD 4811, Australia
14
Centre for Tropical Bioinformatics and Molecular Biology, James Cook University, Cairns, QLD 4811, Australia
*
Author to whom correspondence should be addressed.
Co-Senior authors.
Received: 20 January 2021 / Revised: 7 February 2021 / Accepted: 9 February 2021 / Published: 14 February 2021
(This article belongs to the Special Issue Animal Venoms and Their Components: Molecular Mechanisms of Action)
Melanoma is the main cause of skin cancer deaths, with special emphasis in those cases carrying BRAF mutations that trigger the mitogen-activated protein kinases (MAPK) signaling and unrestrained cell proliferation in the absence of mitogens. Current therapies targeting MAPK are hindered by drug resistance and relapse that rely on metabolic rewiring and Akt activation. To identify new drug candidates against melanoma, we investigated the molecular mechanism of action of the Octopus Kaurna-derived peptide, Octpep-1, in human BRAF(V600E) melanoma cells using proteomics and RNAseq coupled with metabolic analysis. Fluorescence microscopy verified that Octpep-1 tagged with fluorescein enters MM96L and NFF cells and distributes preferentially in the perinuclear area of MM96L cells. Proteomics and RNAseq revealed that Octpep-1 targets PI3K/AKT/mTOR signaling in MM96L cells. In addition, Octpep-1 combined with rapamycin (mTORC1 inhibitor) or LY3214996 (ERK1/2 inhibitor) augmented the cytotoxicity against BRAF(V600E) melanoma cells in comparison with the inhibitors or Octpep-1 alone. Octpep-1-treated MM96L cells displayed reduced glycolysis and mitochondrial respiration when combined with LY3214996. Altogether these data support Octpep-1 as an optimal candidate in combination therapies for melanoma BRAF(V600E) mutations. View Full-Text
Keywords: melanoma BRAF mutation; cancer; combination-therapies; venom-peptide; octopus-peptide melanoma BRAF mutation; cancer; combination-therapies; venom-peptide; octopus-peptide
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MDPI and ACS Style

Moral-Sanz, J.; Fernandez-Rojo, M.A.; Potriquet, J.; Mukhopadhyay, P.; Brust, A.; Wilhelm, P.; Smallwood, T.B.; Clark, R.J.; Fry, B.G.; Alewood, P.F.; Waddell, N.; Miles, J.J.; Mulvenna, J.P.; Ikonomopoulou, M.P. ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations. Toxins 2021, 13, 146. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020146

AMA Style

Moral-Sanz J, Fernandez-Rojo MA, Potriquet J, Mukhopadhyay P, Brust A, Wilhelm P, Smallwood TB, Clark RJ, Fry BG, Alewood PF, Waddell N, Miles JJ, Mulvenna JP, Ikonomopoulou MP. ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations. Toxins. 2021; 13(2):146. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020146

Chicago/Turabian Style

Moral-Sanz, Javier; Fernandez-Rojo, Manuel A.; Potriquet, Jeremy; Mukhopadhyay, Pamela; Brust, Andreas; Wilhelm, Patrick; Smallwood, Taylor B.; Clark, Richard J.; Fry, Bryan G.; Alewood, Paul F.; Waddell, Nicola; Miles, John J.; Mulvenna, Jason P.; Ikonomopoulou, Maria P. 2021. "ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations" Toxins 13, no. 2: 146. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020146

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