Effects Of PAK4 Inhibitor PF-3758309 On Proliferation,Migration And Invasion Of Osteosarcoma Cells

Background and purpose:Osteosarcoma is a mesenchymal tissue-derived malignant tumor,also known as osteosarcoma,which is prone to occur in children and adolescents.Its characteristic is that spindle stromal cells can produce bone like tissue,most of which occur in the metaphysis of long bones of limbs.In the early last century,osteosarcoma meant amputation and death.Since the 1970 s,multidisciplinary treatment including neoadjuvant chemotherapy has improved the survival rate,but the treatment effect is still not ideal for drug-resistant and recurrent patients,and the treatment of osteosarcoma is still facing difficulties.P21 activated kinase 4(PAK4)has been proved to play an important role in tumor development.PAK4 is overexpressed in many different tumors,but its mechanism in osteosarcoma is not clear.This study found that PF-3758309,a new inhibitor of small molecule PAK4,can significantly inhibit the proliferation,invasion and migration of two osteosarcoma cell lines 143 B and U2 OS.PF-3758309 can inhibit the proliferation,invasion and migration of OS cells,And lead to apoptosis of tumor cells.Therefore,we hope to find a new drug that can produce antitumor effect on osteosarcoma cells,try to inhibit the malignant potential of osteosarcoma cells from another signal pathway,and provide a new attempt and opportunity for the treatment of osteosarcoma.Method:Firstly,we analyzed the expression of PAK4 in osteosarcoma cells and normal tissue cells through geo database,and then screened effective PAK4 inhibitors.After screening,we found a new small molecule inhibitor PF-3758309.Then the cells were treated with different concentrations of PAK4 inhibitor PF-3758309.The proliferation,invasion,migration and apoptosis of osteosarcoma cells exposed to different drug concentrations were detected by MTT assay,Transwell assay,cell scratch assay,clone formation assay and flow cytometry.Finally,the expression of osteosarcoma cell related proteins was verified by Western blot assay.Results:In this study,we found that the expression of PAK4 in osteosarcoma was higher than that in normal tissues.Osteosarcoma cells were highly sensitive to PAK4 inhibitor PF-3758309.PF-3758309 could inhibit the activity of OS cells in vitro and had obvious ability to resist the proliferation,invasion and migration of osteosarcoma cells.The antitumor effect of the drug on osteosarcoma cells is time and dose-dependent.The longer the drug exposure time and the higher the drug concentration,the more significant the inhibitory effect is.This process may be related to the drug promoting the apoptosis of osteosarcoma cells.Conclusion:Osteosarcoma cell lines 143 B and U2 OS are sensitive to PAK4 inhibitor PF-3758309 in vitro.PF-3758309 has antitumor effect,can inhibit the proliferation,migration and invasion of OS cells to a certain extent,and promote its apoptosis,indicating that PAK4 inhibitor is expected to become a new drug for the treatment of osteosarcoma.