MAPK signaling regulates c-MYC for melanoma cell adaptation to asparagine restriction

Area of Science:

• Oncology
• Molecular Biology
• Cancer Cell Biology

Background:

• Amino acid restriction is a promising cancer therapy strategy.
• Cancer cells develop resistance mechanisms, hindering treatment efficacy.
• Understanding resistance pathways is crucial for improving cancer therapies.

Purpose of the Study:

• To investigate the mechanisms of resistance to asparagine restriction in melanoma cells.
• To identify novel signaling pathways involved in cancer cell adaptation to nutrient deprivation.
• To explore therapeutic targets for enhancing asparagine restriction strategies.

Main Methods:

• Melanoma cell culture under asparagine restriction.
• Analysis of MAPK signaling pathway activation.
• Assessment of c-MYC protein stability and degradation.
• Measurement of amino acid transporter SLC7A5 expression and function.
• Evaluation of mTORC1 activity.
• Inhibition of the MAPK-c-MYC-SLC7A5 axis.

Main Results:

• MAPK signaling activation in asparagine-restricted melanoma cells inhibits GSK3-β-mediated c-MYC degradation.
• Elevated c-MYC enhances ATF4 translation by upregulating SLC7A5 expression.
• Increased SLC7A5 facilitates essential amino acid uptake, maintaining mTORC1 activity.
• Blocking the MAPK-c-MYC-SLC7A5 axis synergizes with asparagine restriction to inhibit melanoma cell proliferation.

Conclusions:

• Identified a novel MAPK-c-MYC-SLC7A5 signaling axis enabling melanoma cell adaptation to asparagine restriction.
• This axis promotes essential amino acid uptake and sustains mTORC1 activity under nutrient stress.
• Targeting this pathway offers a strategy to overcome resistance and enhance asparagine restriction therapy for melanoma.