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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| Published in: | EMBO reports Vol. 22; no. 3; pp. e51436 - n/a |
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Nature Publishing Group UK
03.03.2021
Springer Nature B.V John Wiley and Sons Inc |
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| 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.
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. |
|---|---|
| AbstractList | 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. This study demonstrates that blocking MAPK cooperates with asparagine restriction to effectively suppress melanoma cell proliferation. 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.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. 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. 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. 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. image 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. 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. This study demonstrates that blocking MAPK cooperates with asparagine restriction to effectively suppress melanoma cell proliferation. |
| Author | Ronai, Ze’ev A Verma, Sachin Scott, David A Yin, Jun Pathria, Gaurav |
| AuthorAffiliation | 1 Cancer Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA 2 Present address: Genentech Inc South San Francisco CA USA |
| AuthorAffiliation_xml | – name: 2 Present address: Genentech Inc South San Francisco CA USA – name: 1 Cancer Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA |
| Author_xml | – sequence: 1 givenname: Gaurav orcidid: 0000-0001-6566-7031 surname: Pathria fullname: Pathria, Gaurav email: gauravpathria@gmail.com organization: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, Genentech Inc – sequence: 2 givenname: Sachin surname: Verma fullname: Verma, Sachin organization: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute – sequence: 3 givenname: Jun surname: Yin fullname: Yin, Jun organization: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute – sequence: 4 givenname: David A orcidid: 0000-0002-8668-2449 surname: Scott fullname: Scott, David A organization: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute – sequence: 5 givenname: Ze’ev A orcidid: 0000-0002-3859-0400 surname: Ronai fullname: Ronai, Ze’ev A email: zeev@ronailab.net organization: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33554439$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | MAPK signaling regulates c-MYC for melanoma cell adaptation to asparagine restriction |
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