期刊
BIOLOGY-BASEL
卷 12, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/biology12050676
关键词
AML; ERK1; 2; mTORC1; AKT; quercetin; rapamycin; 4EBP1; autophagy; eIF2 alpha
类别
mTOR is activated in AML cells, and quercetin and rapamycin inhibit its substrates, P70S6K and 4EBP1. ERK1/2 inhibition enhances the dephosphorylation of mTORC1 substrates and activates AKT. The combined inhibition of ERK1/2 and AKT further enhances the dephosphorylation of 4EBP1 and increases cytotoxicity of quercetin or rapamycin. Additionally, quercetin or rapamycin reduces autophagy, which is related to eIF2a phosphorylation. Therefore, the combined inhibition of mTORC1, ERK1/2, and AKT should be considered in AML treatment.
mTOR is constitutively activated in acute myeloid leukemia (AML) cells, as indicated by the phosphorylation of its substrates, 4EBP1 and P70S6K. Here, we found that quercetin (Q) and rapamycin (Rap) inhibited P70S6K phosphorylation, partially dephosphorylated 4EBP1, and activated ERK1/2 in U937 and THP1, two leukemia cell lines. ERK1/2 inhibition by U0126 induced a stronger dephosphorylation of mTORC1 substrates and activated AKT. The concomitant inhibition of ERK1/2 and AKT further dephosphorylated 4EBP1 and further increased Q- or Rap-mediated cytotoxicity, compared to the single ERK1/2 or AKT inhibition in cells undergoing Q- or Rap-treatments. Moreover, quercetin or rapamycin reduced autophagy, particularly when used in combination with the ERK1/2 inhibitor, U0126. This effect was not dependent on TFEB localization in nuclei or cytoplasm or on the transcription of different autophagy genes, but did correlate with the reduction in protein translation due to a strong eIF2a-Ser51 phosphorylation. Thus, ERK1/2, by limiting 4EBP1 de-phosphorylation and eIF2a phosphorylation, behaves as a paladin of protein synthesis. Based on these findings, the combined inhibition of mTORC1, ERK1/2, and AKT should be considered in treatment of AML.
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