mTORC1/ERK1/2 Interplay Regulates Protein Synthesis and Survival in Acute Myeloid Leukemia Cell Lines

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Mammalian target of rapamycin (mTOR) is constitutively active in acute myeloid leukemia (AML).
• mTOR pathway activation drives leukemia cell proliferation and survival.
• Targeting mTOR is a potential therapeutic strategy for AML.

Purpose of the Study:

• To investigate the effects of quercetin and rapamycin on mTORC1 signaling in AML cell lines.
• To explore the role of ERK1/2 and AKT pathways in modulating mTORC1 activity and cytotoxicity.
• To evaluate the potential of combined inhibition strategies for AML treatment.

Main Methods:

• Treatment of U937 and THP1 AML cell lines with quercetin, rapamycin, U0126 (ERK1/2 inhibitor), and AKT inhibitors.
• Assessment of protein phosphorylation of mTORC1 substrates (4EBP1, P70S6K), ERK1/2, AKT, and eIF2α.
• Analysis of autophagy markers, TFEB localization, and autophagy gene transcription.
• Evaluation of cell viability and cytotoxicity.

Main Results:

• Quercetin and rapamycin inhibited P70S6K phosphorylation and partially dephosphorylated 4EBP1, while activating ERK1/2.
• ERK1/2 inhibition enhanced mTORC1 substrate dephosphorylation and activated AKT.
• Combined inhibition of ERK1/2 and AKT with quercetin or rapamycin increased cytotoxicity and reduced autophagy.
• Reduced protein translation, linked to eIF2α phosphorylation, correlated with decreased autophagy.

Conclusions:

• ERK1/2 acts as a suppressor of mTORC1 substrate dephosphorylation and eIF2α phosphorylation.
• Combined inhibition of mTORC1, ERK1/2, and AKT pathways demonstrates synergistic anti-leukemic effects.
• This multi-targeted approach warrants further investigation for AML therapeutic strategies.