The mTOR inhibitor rapamycin suppresses DNA double-strand break repair.
mTOR (mammalian target of rapamycin) signaling plays a key role in the development of many tumor types. Therefore, mTOR is an attractive target for cancer therapeutics. Although mTOR inhibitors are thought to have radiosensitization activity, the molecular bases remain largely unknown. Here we show that treating MCF7 breast cancer cells with rapamycin (an mTOR inhibitor) results in significant suppression of homologous recombination (HR) and nonhomologous end joining (NHEJ), two major mechanisms required for repairing ionizing radiation-induced DNA DSBs. We observed that rapamycin impaired recruitment of BRCA1 and Rad51 to DNA repair foci, both essential for HR. Moreover, consistent with the suppressive role of rapamycin on both HR and NHEJ, persistent radiation-induced DSBs were detected in cells pretreated with rapamycin. Furthermore, the frequency of chromosome and chromatid breaks was increased in cells treated with rapamycin before and after irradiation. Thus our results show that radiosensitization by mTOR inhibitors occurs via disruption of the major two DNA DSB repair pathways.
Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Blvd., St. Louis, MO 63108, USA.
Honghong
H
Chen
Zhefu
Z
Ma
Robert P
RP
Vanderwaal
Zhihui
Z
Feng
Ignacio
I
Gonzalez-Suarez
Shenming
S
Wang
Jiuqin
J
Zhang
Joseph L
JL
Roti Roti
Susana
S
Gonzalo
Junran
J
Zhang
D019313:BRCA1 Protein / Q000378:metabolism; D001943:Breast Neoplasms / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects*; D005260:Female; D006801:Humans; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D058570:TOR Serine-Threonine Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D020123:Sirolimus
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