title: Inhibition of mTOR sensitizes breast cancer stem cells to radiation-induced repression of self-renewal through the regulation of MnSOD and Akt.
abstract: The sensitization of breast cancer stem cells (BrCSCs) to the inhibitive effects of radiotherapy through adjuvant therapy which targets oncogenic pathways represents a prospective strategy for improving the effect of radiation in patients with triple-negative breast cancer (TNBC). Mammalian target of rapamycin (mTOR) activation is one of the most frequent events in human malignancies, and is critical for sustaining the self‑renewing ability of cancer stem cells (CSCs); inhibition by rapamycin is an effective and promising strategy in anticancer treatments. In the present study, we found that mTOR activity was closely related to the self-renewal ability of BrCSCs, and in triple negative MDA-MB-453 and MDA-MB‑468 cells, rapamycin repression of mTOR phosphorylation decreased the number of mammospheres and helped to sensitize the resistant CSCs to low-dose radiation therapy. By inhibiting mTOR and mitochondrial manganese superoxide dismutase (MnSOD), we confirmed that rapamycin functioned through the mTOR/MnSOD/reactive oxygen species (ROS) signaling pathway, and the existence of Akt governed the rapamycin‑induced asymmetric division (AD) of stem cells in cases of radiation‑treated breast cancer. The synergic effects of rapamycin and low-dose radiation induced the AD of stem cells, which then resulted in a decrease in the number of mammospheres, and both were mediated by MnSOD. Governed by Akt, the consequent inhibition of ROS formation and oxidative stress preserved the AD mode of stem cells, which is critical for an improved radiotherapy response in clinical treatment, as the tumor group is thus easier to eliminate with radiation therapy. We posit that an in-depth understanding of the interaction of radiation with CSCs has enormous potential and will make radiation even better and more effective.
authors.affiliation: Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China.
authors.forename: Yuanhui
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Geriatric Infection and Organ Function Support Laboratory, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Xinpei
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China.
authors.forename: Shanyang
authors.initials: S
authors.lastname: He
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D060049:Asymmetric Cell Division / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000378:metabolism; D011827:Radiation; D011836:Radiation Tolerance / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus