{"title":"MEK抑制剂和Ras-ERK通路显性阴性拮抗剂DA-Raf能阻止KRAS突变癌细胞的迁移和侵袭。","authors":"Aoi Matsuda, Ryuichi Masuzawa, Kazuya Takahashi, Kazunori Takano, Takeshi Endo","doi":"10.1002/cm.21881","DOIUrl":null,"url":null,"abstract":"<p>The Ras-induced ERK pathway (Raf–MEK–ERK signaling cascade) regulates a variety of cellular responses including cell proliferation, survival, and migration. Activating mutations in <i>RAS</i> genes, particularly in the <i>KRAS</i> gene, constitutively activate the ERK pathway, resulting in tumorigenesis, cancer cell invasion, and metastasis. DA-Raf1 (DA-Raf) is a splicing isoform of A-Raf and contains the Ras-binding domain but lacks the kinase domain. Consequently, DA-Raf antagonizes the Ras–ERK pathway in a dominant-negative manner and can serve as a tumor suppressor that targets mutant Ras protein-induced tumorigenesis. We show here that MEK inhibitors and DA-Raf interfere with the in vitro collective cell migration and invasion of human <i>KRAS</i>-mutant carcinoma cell lines, the lung adenocarcinoma A549, colorectal carcinoma HCT116, and pancreatic carcinoma MIA PaCa-2 cells. DA-Raf expression was silenced in these cancer cell lines. All these cell lines had high collective migration abilities and invasion properties in Matrigel, compared with nontumor cells. Their migration and invasion abilities were impaired by suppressing the ERK pathway with the MEK inhibitors U0126 and trametinib, an approved anticancer drug. Expression of DA-Raf in MIA PaCa-2 cells reduced the ERK activity and hindered the migration and invasion abilities. Therefore, DA-Raf may function as an invasion suppressor protein in the <i>KRAS</i>-mutant cancer cells by blocking the Ras–ERK pathway when DA-Raf expression is induced in invasive cancer cells.</p>","PeriodicalId":55186,"journal":{"name":"Cytoskeleton","volume":"82 1-2","pages":"32-44"},"PeriodicalIF":2.4000,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"MEK inhibitors and DA-Raf, a dominant-negative antagonist of the Ras–ERK pathway, prevent the migration and invasion of KRAS-mutant cancer cells\",\"authors\":\"Aoi Matsuda, Ryuichi Masuzawa, Kazuya Takahashi, Kazunori Takano, Takeshi Endo\",\"doi\":\"10.1002/cm.21881\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The Ras-induced ERK pathway (Raf–MEK–ERK signaling cascade) regulates a variety of cellular responses including cell proliferation, survival, and migration. Activating mutations in <i>RAS</i> genes, particularly in the <i>KRAS</i> gene, constitutively activate the ERK pathway, resulting in tumorigenesis, cancer cell invasion, and metastasis. DA-Raf1 (DA-Raf) is a splicing isoform of A-Raf and contains the Ras-binding domain but lacks the kinase domain. Consequently, DA-Raf antagonizes the Ras–ERK pathway in a dominant-negative manner and can serve as a tumor suppressor that targets mutant Ras protein-induced tumorigenesis. We show here that MEK inhibitors and DA-Raf interfere with the in vitro collective cell migration and invasion of human <i>KRAS</i>-mutant carcinoma cell lines, the lung adenocarcinoma A549, colorectal carcinoma HCT116, and pancreatic carcinoma MIA PaCa-2 cells. DA-Raf expression was silenced in these cancer cell lines. All these cell lines had high collective migration abilities and invasion properties in Matrigel, compared with nontumor cells. Their migration and invasion abilities were impaired by suppressing the ERK pathway with the MEK inhibitors U0126 and trametinib, an approved anticancer drug. Expression of DA-Raf in MIA PaCa-2 cells reduced the ERK activity and hindered the migration and invasion abilities. Therefore, DA-Raf may function as an invasion suppressor protein in the <i>KRAS</i>-mutant cancer cells by blocking the Ras–ERK pathway when DA-Raf expression is induced in invasive cancer cells.</p>\",\"PeriodicalId\":55186,\"journal\":{\"name\":\"Cytoskeleton\",\"volume\":\"82 1-2\",\"pages\":\"32-44\"},\"PeriodicalIF\":2.4000,\"publicationDate\":\"2024-06-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cytoskeleton\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cm.21881\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cytoskeleton","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cm.21881","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
MEK inhibitors and DA-Raf, a dominant-negative antagonist of the Ras–ERK pathway, prevent the migration and invasion of KRAS-mutant cancer cells
The Ras-induced ERK pathway (Raf–MEK–ERK signaling cascade) regulates a variety of cellular responses including cell proliferation, survival, and migration. Activating mutations in RAS genes, particularly in the KRAS gene, constitutively activate the ERK pathway, resulting in tumorigenesis, cancer cell invasion, and metastasis. DA-Raf1 (DA-Raf) is a splicing isoform of A-Raf and contains the Ras-binding domain but lacks the kinase domain. Consequently, DA-Raf antagonizes the Ras–ERK pathway in a dominant-negative manner and can serve as a tumor suppressor that targets mutant Ras protein-induced tumorigenesis. We show here that MEK inhibitors and DA-Raf interfere with the in vitro collective cell migration and invasion of human KRAS-mutant carcinoma cell lines, the lung adenocarcinoma A549, colorectal carcinoma HCT116, and pancreatic carcinoma MIA PaCa-2 cells. DA-Raf expression was silenced in these cancer cell lines. All these cell lines had high collective migration abilities and invasion properties in Matrigel, compared with nontumor cells. Their migration and invasion abilities were impaired by suppressing the ERK pathway with the MEK inhibitors U0126 and trametinib, an approved anticancer drug. Expression of DA-Raf in MIA PaCa-2 cells reduced the ERK activity and hindered the migration and invasion abilities. Therefore, DA-Raf may function as an invasion suppressor protein in the KRAS-mutant cancer cells by blocking the Ras–ERK pathway when DA-Raf expression is induced in invasive cancer cells.
期刊介绍:
Cytoskeleton focuses on all aspects of cytoskeletal research in healthy and diseased states, spanning genetic and cell biological observations, biochemical, biophysical and structural studies, mathematical modeling and theory. This includes, but is certainly not limited to, classic polymer systems of eukaryotic cells and their structural sites of attachment on membranes and organelles, as well as the bacterial cytoskeleton, the nucleoskeleton, and uncoventional polymer systems with structural/organizational roles. Cytoskeleton is published in 12 issues annually, and special issues will be dedicated to especially-active or newly-emerging areas of cytoskeletal research.