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ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion

Wei-Ta Chen1, Nancy D Ebelt1, Travis H Stracker2

  • 1Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States.

Elife
|June 2, 2015
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) protein kinase promotes cancer progression by regulating IL-8. ATM depletion reduces cancer cell migration, invasion, and metastasis, revealing a novel role in tumor promotion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Ataxia-telangiectasia mutated (ATM) protein kinase is a key regulator of the DNA damage response (DDR).
  • ATM is traditionally recognized for its tumor-suppressive functions.
  • Emerging evidence suggests ATM may also play roles in cancer progression.

Purpose of the Study:

  • To investigate the role of ATM in cancer cell migration, invasion, and metastasis.
  • To identify downstream targets of ATM involved in promoting cancer progression.
  • To validate ATM and its targets in preclinical cancer models and clinical data.

Main Methods:

  • ATM depletion in metastatic cancer cells.
  • Transcriptional analysis to identify ATM-regulated genes.
  • Validation of IL-8 as an ATM target.
  • Assessment of cell migration and invasion assays.
  • Mouse xenograft models for lung tumor development.
  • Analysis of clinical patient data.

Main Results:

  • ATM depletion significantly reduced cancer cell migration and invasion.
  • A gene network regulated by ATM was identified, including the chemokine IL-8.
  • IL-8 expression was dependent on ATM and regulated by oxidative stress.
  • IL-8 rescued migration and invasion defects in ATM-depleted cells.
  • ATM depletion reduced lung tumor formation in a mouse model.
  • Clinical data confirmed IL-8's association with lung metastasis.

Conclusions:

  • ATM activation by oxidative stress promotes cancer cell migration and invasion through IL-8.
  • These findings establish a novel role for ATM in promoting tumor progression and metastasis.
  • ATM's dual role in tumor suppression and progression offers new therapeutic targets for metastatic cancers.
Keywords:
ATMDNA damageIL-8ROScell biologycell migrationchromosomesgeneshumanmouse

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