ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion
Wei-Ta Chen,
Nancy D Ebelt,
Travis H Stracker,
Blerta Xhemalce,
Carla L Van Den Berg,
Kyle M Miller
Affiliations
Wei-Ta Chen
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States
Nancy D Ebelt
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States; Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, University of Texas at Austin, Austin, United States
Travis H Stracker
Oncology Programme, Institute for Research in Biomedicine, Barcelona, Spain
Blerta Xhemalce
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States
Carla L Van Den Berg
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States; Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, University of Texas at Austin, Austin, United States
Kyle M Miller
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States
Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer-promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion. Transcription analyses identified a gene network, including the chemokine IL-8, regulated by ATM. IL-8 expression required ATM and was regulated by oxidative stress. IL-8 was validated as an ATM target by its ability to rescue cell migration and invasion defects in ATM-depleted cells. Finally, ATM-depletion in human breast cancer cells reduced lung tumors in a mouse xenograft model and clinical data validated IL-8 in lung metastasis. These findings provide insights into how ATM activation by oxidative stress regulates IL-8 to sustain cell migration and invasion in cancer cells to promote metastatic potential. Thus, in addition to well-established roles in tumor suppression, these findings identify a role for ATM in tumor progression.
