title: ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion.
abstract: 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.
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States.
authors.forename: Wei-Ta
authors.initials: WT
authors.lastname: Chen
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Ebelt
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine, Barcelona, Spain.
authors.forename: Travis H
authors.initials: TH
authors.lastname: Stracker
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States.
authors.forename: Blerta
authors.initials: B
authors.lastname: Xhemalce
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States.
authors.forename: Carla L
authors.initials: CL
authors.lastname: Van Den Berg
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Miller
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002458:Cell Fractionation; D002465:Cell Movement / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008156:Luciferases; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D016209:Interleukin-8; D008156:Luciferases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; DNA damage; IL-8; ROS; cell biology; cell migration; chromosomes; genes; human; mouse