PKM2 Promotes Prostate Cancer Metastasis Through Up-regulation Of COX-2 Expression And EMT By Regulation Of ERK1/2 Signaling

Background:Prostate cancer is one of the most common male reproductive system malignancies in the world,and its incidence is the second highest among male malignant tumors worldwide.In the United States,the incidence of prostate cancer in men exceeds that of lung cancer,becoming the most common malignant tumor in men.Patients with prostate cancer are initially sensitive to the treatment of hormonal chemotherapeutic drugs,but over time,most patients develop hormonal resistance,which leads to the metastasis of distal tissues,which leads to the deterioration of the disease.Therefore,studying the metastasis mechanism of prostate cancer is of great significance for the treatment of prostate cancer.Pyruvate kinase 2(PKM2)is an isozyme of pyruvate kinase and can catalyze the conversion of phosphoenolpyruvate(PEP)to pyruvate..Studies have shown that PKM2 is highly expressed in a variety of tumors,recent studies have confirmed that PKM2 can also act as a transcription regulated factor,binding to β-catenin,c-myc,HIF-1α,NF-κB,etc..Cyclooxyenase-2(COX-2)is the rate-limiting enzyme in the process of prostaglandin synthesis,and is highly expressed in a variety of tumors,and promotes tumor proliferation,invasion and migration,inhibits apoptosis,etc.However,whether PKM2 participate in the regulation of invasion and migration of prostate cancer through COX-2 is still to be confirmed.Objective:This study is to investigate the role of PKM2 in the invasion and metastasis of prostate cancer and the mechanism by which COX-2 is involved in the regulation of invasion and migration of prostate cancer.Methods:Prostate cancer cells were infected with lentivirus for overexpression of PKM2,siRNA of PKM2.By Western blot,real-time quantitative fluorescent PCR(RT-qPCR),co-immunoprecipitation(CO-IP),chromatin immunoprecipitation(ChIP),Transwell assay,gelatin zymography and animal experiments were be used to explore the role of PKM2 mediated COX-2 expression in the invasion and metastasis of prostate tumor cells and its mechanism.Results:By analyzing TCGA and Oncomine in the prostate cancer dataset,we found that the expression level of PKM2 in prostate cancer was significantly higher than that in normal tissues and correlated with tumor metastasis and Gleason score.Overexpression of PKM2 expression was found to promote migration and invasion of prostate cancer cells by up-regulating COX-2.In contrast,these effects and COX-2 expression can be inhibited by silencing PKM2.The results of CO-IP experiments showed that PKM2 interacts with ERK1/2 protein,which can promote the phosphorylation of ERK1/2.By using an inhibitor of ERK1/2,the activity of ERK1/2 was significantly inhibited,thereby antagonizing the upregulation of prostate cancer cell migration and invasion due to overexpression of PKM2.ChIP experiments demonstrated that PKM2 contributes to the phosphorylation of c-Jun,a transcription factor downstream of the ERK1/2 pathway that binds to the promoter region of the COX-2 gene,thereby promoting COX-2 expression.Finally,we also demonstrated that inhibition of COX-2 activity blocks tumor metastasis of prostate cancer induced by PKM2 overexpression in vivo.Conclusions:These results suggest that the PKM2-ERK1/2-COX-2 signaling axis plays an important role in the invasion and migration of prostate cancer and may be a potential target for the control of prostate cancer metastasis.