論文

国際誌
2022年2月17日

ACAGT-007a, an ERK MAPK Signaling Modulator, in Combination with AKT Signaling Inhibition Induces Apoptosis in KRAS Mutant Pancreatic Cancer T3M4 and MIA-Pa-Ca-2 Cells.

Cells
  • Golam Iftakhar Khandakar
  • ,
  • Ryosuke Satoh
  • ,
  • Teruaki Takasaki
  • ,
  • Kana Fujitani
  • ,
  • Genzoh Tanabe
  • ,
  • Kazuko Sakai
  • ,
  • Kazuto Nishio
  • ,
  • Reiko Sugiura

11
4
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.3390/cells11040702

The mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol-3 kinase (PI3K)/AKT pathways are dysregulated in various human cancers, including pancreatic ductal adenocarcinoma (PDAC), which has a very poor prognosis due to its lack of efficient therapies. We have previously identified ACAGT-007a (GT-7), an anti-cancer compound that kills ERK-active melanoma cells by inducing ERK-dependent apoptosis. Here, we investigated the apoptosis-inducing effect of GT-7 on three PDAC cell lines and its relevance with the MAPK/ERK and PI3K/AKT signaling pathways. GT-7 induced apoptosis in PDAC cells with different KRAS mutations (MIA-Pa-Ca-2 (KRAS G12C), T3M4 (KRAS Q61H), and PANC-1 (KRAS G12D)), being T3M4 most susceptible, followed by MIA-Pa-Ca-2, and PANC-1 was most resistant to apoptosis induction by GT-7. GT-7 stimulated ERK phosphorylation in the three PDAC cells, but only T3M4 displayed ERK-activation-dependent apoptosis. Furthermore, GT-7 induced a marked down-regulation of AKT phosphorylation after a transient peak in T3M4, whereas PANC-1 displayed the strongest and most sustained AKT activation, followed by MIA-Pa-Ca-2, suggesting that sustained AKT phosphorylation as a determinant for the resistance to GT-7-mediated apoptosis. Consistently, a PI3K inhibitor, Wortmannin, abolished AKT phosphorylation and enhanced GT-7-mediated apoptosis in T3M4 and MIA-Pa-Ca-2, but not in PANC-1, which showed residual AKT phosphorylation. This is the first report that ERK stimulation alone or in combination with AKT signaling inhibition can effectively induce apoptosis in PDAC and provides a rationale for a novel concurrent targeting of the PI3K/AKT and ERK pathways.

リンク情報
DOI
https://doi.org/10.3390/cells11040702
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/35203351
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8869916
ID情報
  • DOI : 10.3390/cells11040702
  • PubMed ID : 35203351
  • PubMed Central 記事ID : PMC8869916

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