Fei Liu1, Yong Zhang2, Yue Dong3, Peifang Ning2, Yanni Zhang4, Han Sun4, Guang Li5. 1. Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, China. 2. Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, China. 3. Department of Radiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, China. 4. Department of Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, China. 5. Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, China. Electronic address: lg13804058616@163.com.
Abstract
AIMS: Abnormally amplified expression of AURKA (aurora kinase A) is closely related to chemo-resistance in human colorectal cancer, lung cancer and leukemia. However, the biological role of AURKA in response to radio-sensitivity in human colorectal cancer is still unknown. Therefore, we evaluated the radio-sensitize ability of perturbation AURKA in human colorectal cancer. MAIN METHODS: The knockdown effect of shAURKA was determined by western blot and qRT-PCR, respectively. Cell growth was determined by CCK-8 and clonogenic assay. Cell migration and metastasis was measured by wound healing assay and transwell invasive assay, respectively. Cell cycle and apoptosis was analyzed by flow cytometry. The alteration of down-stream targets was determined by western blot analysis. KEY FINDINGS: We observed that high-level of AURKA expression is associated with poor prognosis in CRC patients receiving radiotherapy. Knockdown of AURKA significantly sensitizes the efficacy of radiation on the proliferation of HCT116 and HT-29 cells. The combination of AURKA inhibition and radiation could effectively suppress the ability of cell migration and metastasis, but also synergistically induce cellular apoptosis and arrest cell cycle at G2/M phase. Further studies demonstrated that knockdown AURKA markedly enhanced the efficacy of radiation through elevated PARP cleavage and induced AURKA-mediated pro-apoptosis factor BIM. Meanwhile, knockdown of AURKA in combination with radiation synergistically suppressed the regulator in blockage of G2/M phase, CDK2. SIGNIFICANCE: Taken together, our results provide the evidence that targeted inhibition of AURKA could be a promising strategy for enhancing the efficacy of radiation for the treatment of human colorectal cancer.
AIMS: Abnormally amplified expression of AURKA (aurora kinase A) is closely related to chemo-resistance in humancolorectal cancer, lung cancer and leukemia. However, the biological role of AURKA in response to radio-sensitivity in humancolorectal cancer is still unknown. Therefore, we evaluated the radio-sensitize ability of perturbation AURKA in humancolorectal cancer. MAIN METHODS: The knockdown effect of shAURKA was determined by western blot and qRT-PCR, respectively. Cell growth was determined by CCK-8 and clonogenic assay. Cell migration and metastasis was measured by wound healing assay and transwell invasive assay, respectively. Cell cycle and apoptosis was analyzed by flow cytometry. The alteration of down-stream targets was determined by western blot analysis. KEY FINDINGS: We observed that high-level of AURKA expression is associated with poor prognosis in CRCpatients receiving radiotherapy. Knockdown of AURKA significantly sensitizes the efficacy of radiation on the proliferation of HCT116 and HT-29 cells. The combination of AURKA inhibition and radiation could effectively suppress the ability of cell migration and metastasis, but also synergistically induce cellular apoptosis and arrest cell cycle at G2/M phase. Further studies demonstrated that knockdown AURKA markedly enhanced the efficacy of radiation through elevated PARP cleavage and induced AURKA-mediated pro-apoptosis factor BIM. Meanwhile, knockdown of AURKA in combination with radiation synergistically suppressed the regulator in blockage of G2/M phase, CDK2. SIGNIFICANCE: Taken together, our results provide the evidence that targeted inhibition of AURKA could be a promising strategy for enhancing the efficacy of radiation for the treatment of humancolorectal cancer.