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Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis

Hyeon-Ok Jin1, Sung-Eun Hong2, Ji-Young Kim2

  • 1KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Republic of Korea. hyeonok@kirams.re.kr.

Cell Death & Disease
|December 4, 2021
PubMed

Insights

Amino acid deprivation activates AKT signaling in non-small cell lung cancer (NSCLC) via the GCN2/ATF4/REDD1 pathway. REDD1 is crucial for this activation and sensitizes NSCLC cells to radiotherapy when glutamine is deprived.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Cellular Metabolism

Background:

  • Amino acid availability is critical for cell survival and is sensed by key signaling pathways like GCN2 and mTORC1.
  • The precise mechanisms linking amino acid sensing to cancer cell survival, particularly AKT activation, remain incompletely understood.

Purpose of the Study:

  • To investigate the role of specific amino acid deprivation in activating AKT signaling in non-small cell lung cancer (NSCLC) cells.
  • To elucidate the molecular axis responsible for AKT activation under conditions of low amino acid availability.

Main Methods:

  • Utilized non-small cell lung cancer (NSCLC) cell lines.
  • Deprived cells of individual amino acids to assess effects on AKT activation.
  • Employed CRISPR-Cas9 gene editing to create REDD1-knockout cells.
  • Evaluated the impact of REDD1 knockout on AKT activation and radiosensitivity under amino acid deprivation.

Main Results:

  • Deprivation of glutamine, arginine, methionine, and lysine induced AKT activation in NSCLC cells.
  • AKT activation was mediated by the GCN2/ATF4/REDD1 axis, leading to mTORC2 activation.
  • REDD1 knockout abrogated AKT activation upon amino acid deprivation.
  • REDD1-deficient cells showed increased sensitivity to radiotherapy when cultured under glutamine deprivation.

Conclusions:

  • The GCN2/ATF4/REDD1 axis plays a pivotal role in promoting cancer cell survival signals in response to amino acid deprivation.
  • Targeting the REDD1-mediated pathway could represent a novel therapeutic strategy for NSCLC, potentially enhancing radiotherapy efficacy.

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