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

ABSTRACT: Amino acid restriction is among promising potential cancer treatment strategies. However, cancer cells employ a multitude of mechanisms to mount resistance to amino acid restriction, which impede the latter's clinical development. Here we show that MAPK signaling activation in asparagine-restricted melanoma cells impairs GSK3-β-mediated c-MYC degradation. In turn, elevated c-MYC supports ATF4 translational induction by enhancing the expression of the amino acid transporter SLC7A5, increasing the uptake of essential amino acids, and the subsequent maintenance of mTORC1 activity in asparagine-restricted melanoma cells. Blocking the MAPK-c-MYC-SLC7A5 signaling axis cooperates with asparagine restriction to effectively suppress melanoma cell proliferation. This work reveals a previously unknown axis of cancer cell adaptation to asparagine restriction and informs mechanisms that may be targeted for enhanced therapeutic efficacy of asparagine limiting strategies.

SUBMITTER: Pathria G

PROVIDER: S-EPMC7926261 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Pathria Gaurav G Verma Sachin S Yin Jun J Scott David A DA Ronai Ze'ev A ZA

EMBO reports 20210208 3

Amino acid restriction is among promising potential cancer treatment strategies. However, cancer cells employ a multitude of mechanisms to mount resistance to amino acid restriction, which impede the latter's clinical development. Here we show that MAPK signaling activation in asparagine-restricted melanoma cells impairs GSK3-β-mediated c-MYC degradation. In turn, elevated c-MYC supports ATF4 translational induction by enhancing the expression of the amino acid transporter SLC7A5, increasing the ...[more]

PMID: 33554439

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MAPK Signaling Regulates c-MYC for Melanoma Cell Adaptation to Asparagine Restriction

Project description:Amino acid restriction is among promising potential cancer treatment strategies. However, cancer cells employ a multitude of mechanisms to mount resistance to amino acid restriction, which impede the latter's clinical development. Here we show that MAPK signaling activation in asparagine-restricted melanoma cells impairs GSK3-?-mediated c-MYC degradation. In turn, elevated c-MYC supports ATF4 translational induction by enhancing the expression of the amino acid transporter SLC7A5, increasing the uptake of essential amino acids, and the subsequent maintenance of mTORC1 activity in asparagine-restricted melanoma cells. Blocking the MAPK-c-MYC-SLC7A5 signaling axis cooperates with asparagine restriction to effectively suppress melanoma cell proliferation. This work reveals a previously unknown axis of cancer cell adaptation to asparagine restriction and informs mechanisms that may be targeted for enhanced therapeutic efficacy of asparagine limiting strategies.

| S-SCDT-EMBOR-2020-51436V1 | biostudies-other

Translational reprogramming marks adaptation to asparagine restriction in cancer.

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Asparagine bioavailability regulates the translation of MYC oncogene.

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Combating acquired resistance to MAPK inhibitors in melanoma by targeting Abl1/2-mediated reactivation of MEK/ERK/MYC signaling.

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A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of <i>BRAF</i>-mutated Melanoma to MAPK Inhibitors.

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The evolutionarily conserved MAPK/Erk signaling promotes ancestral T-cell immunity in fish via c-Myc-mediated glycolysis.

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