MET And DRP1 As Potential Targeted Therapy For Malignant Pleural Mesothelioma

Malignant pleural mesothelioma(MPM)is an aggressive form of cancer with very poor prognosis.MPM is an extremely difficult disease to treat with the median overall survival ranging between 9 and 17 months[1]MPM remains a serious public health problem as it has steadily increased in worldwide cases over the past decade and unfortunately,is predicted to rise further[2]Moreover,MPM is extremely dificult to treat with little treatment option.Therefore,new approaches and targeted therapeutics are urgently needed to treat and manage this burgeoning disease.The receptor tyrosine kinase MET plays a crucial role in cancer biology including cell survival,cell growth,angiogenesis,and metastasis[3].MET is overexpressed or activated in many cancers,including MPM and non-small cell lung cancers(NSCLC).MET overexpression is commonly detected in NSCLC patients showing resistance to EGFR inhibitors erlotinib or gefitinib.However,this resistance can be overcome by combining with a MET inhibitor PHA665752 with improve clinical outcomes[4-7].MGCD265 is very possible to be an attractive method for MPM therapy.Mitochondria has emerged to play an essential role in tumorigenesis[8-10],Cancer cells can alter dynamics,the bioenergetics and biosynthetic properties of mitochondrial to support cell proliferation,cell migration and to confer therapeutic resistance by inhibiting apoptosis[11,12].DRP1 is a key component of the mitochondrial fission machinery and emerged to be an attractive therapeutic target.Furthermore,biochemical and molecular differences in cancer cell mitochondria have led to the development of therapeutics targeting mitochondria proteins,such as Mdivi-1,DRP1 inhibitor.To investigate the role of MET and DRP1 in MPM,we determine the relation between MET and DRP1,and combine MGCD265 and Mdivi1 to treat MPM cells.Methods:Detect the expression level of MET and DRP1 in MPM.Transfect specific si-RNA to knockdown gene expression,determine expression level of apoptotic protein and mitochondrial relative proteins.Transfect MET-GFP to upregulate MET expression.Cell viability was detected by CCK-8 kit.Determine the expression of DRP1 and phosphorylated-DRP1 after MGCD265 treatment via Western Blot and Immunofluorescence.Detect mitochondrial morphology change by staining with Mito tracker in confocal microscope.Drug combination efficacy were analyzed by compusy software.Migration,invasion and flow cytometry assay were performed.Results:MET and DRP1,antiapoptotic oncogene,are expressed highly in MPM.Knockdown MET,the expression of p-DRP1 and FIS-1 was decreased.Upregulated MET,expression of p-DRP1 and FIS-1 was increased.MGCD265 inhibits mitochondrial fission and elongate mitochondrial length.Combination of MGCD265 and Mdivi-1 induce synergistic effect in MPM,attenuate MPM cells proliferation,migration and invasion.Conclusion:MET and DRP1 play crucial role in MPM.MET can regulate DRP1 expression and effect mitochondrial morphology and function.Combination of MGCD265 and Mdivi-1 induces synergistic effect in MPM.It may provide new insight for MPM treatment.