mEAK-7 Forms an Alternative mTOR Complex with DNA-PKcs in Human Cancer

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Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells
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Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells

Published on: June 9, 2020

11.7K

Joe Truong Nguyen1, Fatima Sarah Haidar1, Alexandra Lucienne Fox1

  • 1Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA.

Iscience
|July 10, 2019
PubMed

Insights

MTOR associated protein, eak-7 homolog (mEAK-7), is elevated in non-small-cell lung cancer and promotes cancer stem cell growth. mEAK-7 forms a novel complex with DNA-PKcs to regulate mTOR signaling, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Mechanistic target of rapamycin (mTOR) signaling is crucial in cell growth and proliferation.
  • The role of MTOR associated protein, eak-7 homolog (mEAK-7) in human cancer remains largely unknown.
  • mEAK-7 is known to activate mTOR signaling through an alternative complex.

Purpose of the Study:

  • To investigate the role of mEAK-7 in non-small-cell lung carcinoma (NSCLC).
  • To elucidate the molecular mechanism by which mEAK-7 influences cancer cell behavior.
  • To identify potential therapeutic targets within the mEAK-7/mTOR pathway in NSCLC.

Main Methods:

  • Comparative analysis of mEAK-7 and mTOR signaling in NSCLC tissues versus normal tissues.
  • Characterization of mEAK-7 and mTOR signaling in cancer stem cells (CD44+/CD90+).
  • Assessment of mEAK-7's role in clonogenic potential and spheroid formation.
  • Investigation of the interaction between mEAK-7 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) using biochemical assays and irradiation treatments.
  • Evaluation of the impact of DNA-PKcs inhibition or knockout on downstream signaling pathways.

Main Results:

  • mEAK-7 and mTOR signaling were significantly elevated in NSCLC tumors and metastatic lymph nodes.
  • Cancer stem cells exhibited increased mEAK-7 levels and activated mTOR signaling.
  • mEAK-7 was essential for cancer cell clonogenic potential and spheroid formation.
  • mEAK-7 directly associates with DNA-PKcs, and this interaction is enhanced by X-ray irradiation.
  • Inhibition or knockout of DNA-PKcs disrupted the mEAK-7/DNA-PKcs complex, leading to reduced S6K2 activity and abrogated mTOR signaling.

Conclusions:

  • mEAK-7 plays a critical role in the progression of non-small-cell lung carcinoma.
  • mEAK-7 forms an alternative mTOR complex with DNA-PKcs to regulate S6K2 signaling in cancer cells.
  • The mEAK-7/DNA-PKcs complex represents a novel therapeutic target for NSCLC treatment.
Keywords:
Biological SciencesCancerCell Biology

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