title: Aurora kinase a suppresses metabolic stress-induced autophagic cell death by activating mTOR signaling in breast cancer cells.
abstract: Aberrant Aur-A signaling is associated with tumor malignant behaviors. However, its involvement in tumor metabolic stress is not fully elucidated. In the present study, prolonged nutrient deprivation was conducted into breast cancer cells to mimic metabolic stress in tumors. In these cells, autophagy was induced, leading to caspase-independent cell death, which was blocked by either targeted knockdown of autophagic gene ATG5 or autophagy inhibitor 3-Methyladenine (3-MA). Aur-A overexpression mediated resistance to autophagic cell death and promoted breast cancer cells survival when exposed to metabolic stress. Moreover, we provided evidence that Aur-A suppressed autophagy in a kinase-dependent manner. Furthermore, we revealed that Aur-A overexpression enhanced the mammalian target of rapamycin (mTOR) activity under metabolic stress by inhibiting glycogen synthase kinase 3β (GSK3β). Inhibition of mTOR activity by rapamycin sensitized Aur-A-overexpressed breast cancer cells to metabolic stress-induced cell death. Consistently, we presented an inverse correlation between Aur-A expression (high) and autophagic levels (low) in clinical breast cancer samples. In conclusion, our data provided a novel insight into the cyto-protective role of Aur-A against metabolic stress by suppressing autophagic cell death, which might help to develop alternative cell death avenues for breast cancer therapy.
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Xu
authors.affiliation: Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Peng
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Kamran
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Si-Si
authors.initials: SS
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Wang
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Hong-Jiang
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Thyroid Surgery, the Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Yong-Fu
authors.initials: YF
authors.lastname: Zhao
authors.affiliation: Department of Critical Care Medicine, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Xian-Yao
authors.initials: XY
authors.lastname: Wan
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China. Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D064096:Aurora Kinase A / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D020552:Comet Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D046529:Microscopy, Electron, Transmission; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D034741:RNA, Small Interfering; C546842:MTOR protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A; D058570:TOR Serine-Threonine Kinases