title: Dual Targeting of Akt and mTORC1 Impairs Repair of DNA Double-Strand Breaks and Increases Radiation Sensitivity of Human Tumor Cells.
abstract: Inhibition of mammalian target of rapamycin-complex 1 (mTORC1) induces activation of Akt. Because Akt activity mediates the repair of ionizing radiation-induced DNA double-strand breaks (DNA-DSBs) and consequently the radioresistance of solid tumors, we investigated whether dual targeting of mTORC1 and Akt impairs DNA-DSB repair and induces radiosensitization. Combining mTORC1 inhibitor rapamycin with ionizing radiation in human non-small cell lung cancer (NSCLC) cells (H661, H460, SK-MES-1, HTB-182, A549) and in the breast cancer cell line MDA-MB-231 resulted in radiosensitization of H661 and H460 cells (responders), whereas only a very slight effect was observed in A549 cells, and no effect was observed in SK-MES-1, HTB-182 or MDA-MB-231 cells (non-responders). In responder cells, rapamycin treatment did not activate Akt1 phosphorylation, whereas in non-responders, rapamycin mediated PI3K-dependent Akt activity. Molecular targeting of Akt by Akt inhibitor MK2206 or knockdown of Akt1 led to a rapamycin-induced radiosensitization of non-responder cells. Compared to the single targeting of Akt, the dual targeting of mTORC1 and Akt1 markedly enhanced the frequency of residual DNA-DSBs by inhibiting the non-homologous end joining repair pathway and increased radiation sensitivity. Together, lack of radiosensitization induced by rapamycin was associated with rapamycin-mediated Akt1 activation. Thus, dual targeting of mTORC1 and Akt1 inhibits repair of DNA-DSB leading to radiosensitization of solid tumor cells.
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Eberhard Karls University Tuebingen, Roentgenweg 11, 72076, Tuebingen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Holler
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Grottke
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Eberhard Karls University Tuebingen, Roentgenweg 11, 72076, Tuebingen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mueck
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Eberhard Karls University Tuebingen, Roentgenweg 11, 72076, Tuebingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Manes
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jücker
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Eberhard Karls University Tuebingen, Roentgenweg 11, 72076, Tuebingen, Germany.
authors.forename: H Peter
authors.initials: HP
authors.lastname: Rodemann
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Eberhard Karls University Tuebingen, Roentgenweg 11, 72076, Tuebingen, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Toulany
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus