Aurora-A controls cancer cell radio- and chemoresistance via ATM/Chk2-mediated DNA repair networks.
High expression of Aurora kinase A (Aurora-A) has been found to confer cancer cell radio- and chemoresistance, however, the underlying mechanism is unclear. In this study, by using Aurora-A cDNA/shRNA or the specific inhibitor VX680, we show that Aurora-A upregulates cell proliferation, cell cycle progression, and anchorage-independent growth to enhance cell resistance to cisplatin and X-ray irradiation through dysregulation of DNA damage repair networks. Mechanistic studies showed that Aurora-A promoted the expression of ATM/Chk2, but suppressed the expression of BRCA1/2, ATR/Chk1, p53, pp53 (Ser15), H2AX, γH2AX (Ser319), and RAD51. Aurora-A inhibited the focus formation of γH2AX in response to ionizing irradiation. Treatment of cells overexpressing Aurora-A and ATM/Chk2 with the ATM specific inhibitor KU-55933 increased the cell sensitivity to cisplatin and irradiation through increasing the phosphorylation of p53 at Ser15 and inhibiting the expression of Chk2, γH2AX (Ser319), and RAD51. Further study revealed that BRCA1/2 counteracted the function of Aurora-A to suppress the expression of ATM/Chk2, but to activate the expression of ATR/Chk1, pp53, γH2AX, and RAD51, leading to the enhanced cell sensitivity to irradiation and cisplatin, which was also supported by the results from animal assays. Thus, our data provide strong evidences that Aurora-A and BRCA1/2 inversely control the sensitivity of cancer cells to radio- and chemotherapy through the ATM/Chk2-mediated DNA repair networks, indicating that the DNA repair molecules including ATM/Chk2 may be considered for the targeted therapy against cancers with overexpression of Aurora-A.
Cancer Institute, Fudan University Shanghai Cancer Center,  270 Dong'an Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China.
Huizhen
H
Sun
Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China.
Yan
Y
Wang
Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China.
Ziliang
Z
Wang
Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China.
Jiao
J
Meng
Cancer Institute, Fudan University Shanghai Cancer Center,  270 Dong'an Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China.
Zihao
Z
Qi
Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China; The Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China. Electronic address: yanggong@fudan.edu.cn.
Gong
G
Yang
D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology*; D064096:Aurora Kinase A / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D064593:Heterografts; D006801:Humans; D011836:Radiation Tolerance / Q000502:physiology*
D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576917:AURKA protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D064096:Aurora Kinase A; C578634:CHEK2 protein, human
ATM; Aurora-A; BRCA1; BRCA2; Chk2; Radio- and chemo-resistance