Effects And Mechanisms Of AXL On The Resistance Of Prostate Cancer To Docetaxel Therapy

Objective:Resistance to docetaxel is a major clinical problem in advanced prostate cancer.The overexpression of AXL receptor tyrosine kinase(AXL)has been correlated with chemotherapeutic drug resistance.However,the role of AXL expression in docetaxel resistance in prostate cancer is yet unclear.Methods:PC3-DR and DU145-DR cells were estimated via gradually increasing concentrations of docetaxel.PC-3 and DU145 cells/PC3-DR and DU145-DR cells were transfected with AXL-ShRNA or AXL-SiRNA,respectively,which were confirmed to be effective by WB or realtime-PCR.CCK8/MTT and flow cytometry were used to examine the the proliferation,apoptosis rate and the cycle distribution after different treatment.Transwell assay was used to analyze the ability of the cells after exposing to different treatment.In vivo animal models for CRPC resistance can be obtained by subcutaneous injection of DU145-DR cells.The proliferation and apoptosis was further analyzed using HE sliced detection and tunel detection.The levels of the related proteins were detected by WB,IHC and IF.Results:In this study,we demonstrate that AXL is overexpressed and activated independent of Gas6 in docetaxel-resistant prostate cancer cells(PC3-DR and DU 145-DR).Moreover,we show that forced overexpression of AXL in PC3 and DU 145 cells is sufficient to induce resistance to docetaxel in these cell lines.Notably,genetic or pharmacologic inhibition of AXL in the resistant models suppressed cell proliferation,migration,invasion,and tumor growth,and these effects were significantly augmented when AXL inhibition was combined with docetaxel treatment.Mechanistically,we found that AXL inhibition led to reversion of the epithelial-mesenchymal transition(EMT)phenotype and decreased the expression of ATP-binding cassette B1(ABCB1)and Bcl2.The percentage in the G2/M phase of resistant cells in the combination of MP470 and docetaxel were also found to be remarkably higher than single drug.Conclusion:Overall,our results identify AXL as an important mediator of docetaxel resistance in prostate cancer.We propose that AXL-targeted therapy,in combination with docetaxel,has the potential to improve the response to docetaxel therapy and reduce resistance induced by prolonged docetaxel therapy in prostate cancer.