title: Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks.
abstract: Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly, mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA-damaging agents; however, the molecular mechanism is not well understood. We found that an mTOR-selective kinase inhibitor, AZD8055, significantly enhanced sensitivity of a pediatric rhabdomyosarcoma xenograft to radiotherapy and sensitized rhabdomyosarcoma cells to the DNA interstrand cross-linker (ICL) melphalan. Sensitization correlated with drug-induced downregulation of a key component of the Fanconi anemia pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1. Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2 checkpoint in response to ICL and that mTOR signaling promotes ICL-induced ATM-Chk2 checkpoint activation by sustaining FANCD2. In FANCD2-deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced DNA damage, and FANCD2-deficient cells showed impaired ATM-Chk2 and ATR-Chk1 activation, which was rescued by reintroduction of wild-type FANCD2. Pharmacologic inhibition of PI3K-mTOR-AKT pathway in Rh30 rhabdomyosarcoma cells attenuated ICL-induced activation of ATM, accompanied with the decrease of FANCD2. These data suggest that the mTOR pathway may promote the repair of DNA double-strand breaks by sustaining FANCD2 and provide a novel mechanism of how the Fanconi anemia pathway modulates DNA damage response and repair.
authors: Center for Childhood Cancer & Blood Diseases, The Research Institute, Nationwide Children's Hospital, 700 Children's Drive,ResearchBuilding II,Columbus,OH 43205, USA.
authors: Changxian
authors: C
authors: Shen
authors: Duane
authors: D
authors: Oswald
authors: Doris
authors: D
authors: Phelps
authors: Hakan
authors: H
authors: Cam
authors: Christopher E
authors: CE
authors: Pelloski
authors: Qishen
authors: Q
authors: Pang
authors: Peter J
authors: PJ
authors: Houghton
mesh_terms: D000293:Adolescent; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; C546842:MTOR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D058570:TOR Serine-Threonine Kinases
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