Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer.
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to be activated by radiation. The mammalian target of rapamycin (mTOR) is downstream of Akt, and we investigated the effects of radiation on Akt/mTOR signaling in breast cancer cell models. RAD001 (everolimus), a potent derivative of the mTOR inhibitor rapamycin, was used to study the effects of mTOR inhibition, as the role of mTOR inhibition in enhancing radiation remains unexplored. RAD001 decreased clonogenic cell survival in both breast cancer cell lines MDA-MB-231 and MCF-7, although the effect is greater in MDA-MB-231 cells. Irradiation induced Akt and mTOR signaling, and this signaling is attenuated by RAD001. The radiation-induced signaling activation is mediated by PI3K because inhibition of PI3K with LY294002 inhibited the increase in downstream mTOR signaling. Additionally, caspase-dependent apoptosis is an important mechanism of cell death when RAD001 is combined with 3 Gy radiation, as shown by induction of caspase-3 cleavage. An increase in G(2)-M cell cycle arrest was seen in the combination treatment group when compared with controls, suggesting that cell cycle arrest may have been a contributing factor in the increased radiosensitization seen in this study. We conclude that RAD001 attenuates radiation-induced prosurvival Akt/mTOR signaling and enhances the cytotoxic effects of radiation in breast cancer cell models, showing promise as a method of radiosensitization of breast cancer.
Albert
Jeffrey M
JM
Department of Radiation Oncology, Vanderbilt University, B-902 The Vanderbilt Clinic, 1301 22nd Avenue South, Nashville, TN 37232-5671, USA.
Kim
Kwang Woon
KW
Cao
Carolyn
C
Lu
Bo
B
D001943:Breast Neoplasms / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival / Q000528:radiation effects; D000068338:Everolimus; D005260:Female; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism* / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D011838:Radiation-Sensitizing Agents; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020123:Sirolimus