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

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...

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Veröffentlicht in:EMBO reports Jg. 22; H. 3; S. e51436 - n/a
Hauptverfasser: Pathria, Gaurav, Verma, Sachin, Yin, Jun, Scott, David A, Ronai, Ze’ev A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 03.03.2021
Springer Nature B.V
John Wiley and Sons Inc
Schlagworte:
Acid resistance
Adaptation
Amino acids
Asparagine
ATF4
Cancer
Cell activation
Cell growth
Cell Line, Tumor
Cell Proliferation
c‐MYC
Degradation
EMBO03
EMBO21
Glycogen Synthase Kinase 3
Humans
MAP kinase
MAPK
Mechanistic Target of Rapamycin Complex 1 - genetics
Mechanistic Target of Rapamycin Complex 1 - metabolism
Melanoma
Melanoma - genetics
mTORC1
Myc protein
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Signal Transduction
Signaling
melanoma
MAPK
c-MYC
mTORC1
ATF4
ISSN:1469-221X, 1469-3178, 1469-3178
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Zusammenfassung: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. SYNOPSIS This study demonstrates that blocking MAPK cooperates with asparagine restriction to effectively suppress melanoma cell proliferation. MAPK activation impairs GSK3-β mediated c-MYC degradation in asparagine-restricted melanoma cells. c-MYC promotes SLC7A5 expression to increase the uptake of essential amino acids. Essential amino acids induce mTORC1 activity, supporting ATF4 translation. Blocking the MAPK-c-MYC-SLC7A5-mTORC1 signaling axis cooperates with asparagine restriction to restrict melanoma cell proliferation. Graphical Abstract This study demonstrates that blocking MAPK cooperates with asparagine restriction to effectively suppress melanoma cell proliferation.
Bibliographie:ObjectType-Article-1
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ISSN:1469-221X
1469-3178
1469-3178
DOI:10.15252/embr.202051436