ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations.
Toxins (Basel)
; 13(2)2021 02 14.
Article
em En
| MEDLINE
| ID: mdl-33672955
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Sirolimo
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Proteínas Proto-Oncogênicas B-raf
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MAP Quinases Reguladas por Sinal Extracelular
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Inibidores de Proteínas Quinases
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Alvo Mecanístico do Complexo 1 de Rapamicina
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Melanoma
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Mutação
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article