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MAPK signaling regulates c‐MYC for melanoma cell adaptation to asparagine restriction
Author(s) -
Pathria Gaurav,
Verma Sachin,
Yin Jun,
Scott David A,
Ronai Ze’ev A
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202051436
Subject(s) - asparagine , mtorc1 , mapk/erk pathway , cellular adaptation , amino acid , cancer research , cancer cell , biology , carcinogenesis , cell growth , signal transduction , microbiology and biotechnology , biochemistry , cancer , pi3k/akt/mtor pathway , genetics , gene
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.