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ERK 和 mTORC1 抑制剂增强 Octpep-1 毒液衍生肽在黑色素瘤 BRAF(V600E)突变中的抗癌能力。

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

机构信息

Translational Venomics Group, Madrid Institute for Advanced Studies in Food, E28049 Madrid, Spain.

Hepatic Regenerative Medicine Group, Madrid Institute for Advanced Studies in Food, E28049 Madrid, Spain.

出版信息

Toxins (Basel). 2021 Feb 14;13(2):146. doi: 10.3390/toxins13020146.

DOI:10.3390/toxins13020146
PMID:33672955
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7918145/
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 -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.

摘要

黑色素瘤是皮肤癌死亡的主要原因，特别是那些携带 BRAF 突变的病例，这些突变会触发丝裂原激活蛋白激酶（MAPK）信号通路，并在没有丝裂原的情况下导致不受控制的细胞增殖。目前针对 MAPK 的治疗方法受到耐药性和复发的阻碍，这些耐药性和复发依赖于代谢重排和 Akt 的激活。为了寻找针对黑色素瘤的新药物候选物，我们使用蛋白质组学和 RNAseq 结合代谢分析研究了衍生肽 Octpep-1 在人 BRAF(V600E)黑色素瘤细胞中的作用机制。荧光显微镜验证了带有荧光素的 Octpep-1 标记物进入 MM96L 和 NFF 细胞，并优先分布在 MM96L 细胞的核周区。蛋白质组学和 RNAseq 显示，Octpep-1 靶向 MM96L 细胞中的 PI3K/AKT/mTOR 信号通路。此外，与单独使用抑制剂或 Octpep-1 相比，Octpep-1 与雷帕霉素（mTORC1 抑制剂）或 LY3214996（ERK1/2 抑制剂）联合使用可增强对 BRAF(V600E)黑色素瘤细胞的细胞毒性。用 Octpep-1 处理的 MM96L 细胞在与 LY3214996 联合使用时显示出减少的糖酵解和线粒体呼吸作用。总之，这些数据支持 Octpep-1 作为 BRAF(V600E)突变黑色素瘤联合治疗的最佳候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50eb/7918145/6ab55fba6adf/toxins-13-00146-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50eb/7918145/fc77b0806f39/toxins-13-00146-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50eb/7918145/6ab55fba6adf/toxins-13-00146-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50eb/7918145/173125a19d78/toxins-13-00146-g0A1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50eb/7918145/6ca16ddfc2e4/toxins-13-00146-g001.jpg
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