Regulation Of Metabolism And Oxidative Stress By Aurora A In Cancer

Aurora A is a serine/threonine protein kinase that plays an important role in the mitotic phase.It has been reported that Aurora A is highly expressed in many tumors and is related to the poor prognosis of patients.Therefore,Aurora A is considered to be an important target for cancer therapy,and a variety of Aurora A inhibitors are currently undergoing clinical trials.The expression of Aurora A in tumors has significantly increased in S/G2 phase.More and more evidences show that it is involved in the regulation of various biological behaviors in S/G2 phase,but the mechanism is unknown.Therefore,we hope to find its new binding substrate,and explore new biological function of Aurora A.In the chapter 1,we found that Aurora A can be involved in regulating tumor glycolysis.Our results show that Aurora A can directly bind to Lactate dehydrogenase B(LDHB),a metabolic enzyme involved in glycolysis,and phosphorylate Ser162 of LDHB.After LDHB is phosphorylated by Aurora A,its preference of enzyme activity was changed,from preference for catalyzing lactic acid to pyruvate to pyruvate to lactic acid.The change of LDHB enzyme activity preference promotes the production of lactic acid and the uptake of glucose,which in turn promotes tumor glycolysis.Further research shows that blocking S162 phosphorylation by expression of a LDHB-S162A mutant inhibited glycolysis and cell cycle progression in cancer cells.In vitro proliferation and cloning formation experiments and in vivo xenograft models,LDHB S162A significantly inhibited the tumorigenic ability of tumor cells,further demonstrating that Aurora A phosphorylated LDHB promotes the development of tumors.In summary,we discovered LDHB as a new substrate of Aurora A.Aurora A can phosphorylate LDHB to promote glycolysis of tumor cells.At the same time,this is also the first report of post-translational modification of LDHB.In the chapter 2,we found that Aurora A is involved in the regulation of oxidative stress in tumor cells.Metabolic abnormalities,oncogenic activations,inactivation of tumor suppressor or intervention of chemotheraprutic drugs in cancer cells contribute to the accumulation of ROS,which at high levels lead to biomolecular damage and even cell demise.Using western blot assay,we found that under oxidative stress,the phosphorylation level of Aurora A increased significantly,and the increase in phosphorylation level was independent of the cell cycle.At the same time,By using in vitro kinase experiments,we found that increased phosphorylation of Aurora A promoted its kinase activity.Mechanistically,we have revealed that ROS can promote the oxidative modification of Aurora A to increase its autophosphorylation between molecules to improve its activity.By using cell proliferation and clone formation experiments,we found that inhibiting the activity of Aurora A would significantly.inhibit the proliferation and survival of tumor cells under oxidative stress.Therefore,these results clarified that the increase of Aurora A activity can promote tumor cells resistance to ROS.Together,we revealed the new biological function of Aurora A independent of mitosis.Based on the study of these new biological functions,it will deepen the understanding of the roles of Aurora A in tumorigenesis and development.It will provide new strategies of clinical therapeutic,which use Aurora A as a tumor therapy target.