Deregulation Of Exo70 Facilitates Cisplatin Resistance In Epithelial Ovarian Cancer By Promoting Cisplatin Efflux

Epithelial ovarian cancer(EOC)is a common gynecological malignant tumor,which accounting for 90%of the ovarian cancer.Due to the occult onset,patients were diagnosed at an advanced stage and leading to a poor prognosis.Platinum drugs are the first choice for clinical treatment of ovarian cancer.However,the recurrence caused by drug resistance severely reduces the quality of ovarian cancer patients.Exo70 is a key member of the exocyst,which participates in the construction of the extracellular secretory complex,mediates the anchoring and fusion of intracellular transport vesicles.Studies have shown that the exocytosis is beneficial to reduce the accumulation of platinum drugs,suggesting the possibility that Exo70 involved in platinum resistance of EOC.In this article,we found that Exo70 is associated with cisplatin resistance in EOC.Analysis of clinical samples showed that Exo70 was highly expressed in epithelial ovarian cancer tissues,which affected progression-free survival of patients with EOC under platinum-based chemotherapy.Further molecular mechanism studies showed that Exo70 can promote the exocytosis of cisplatin by EOC cells in a manner independent of ATP7 A and ATP7B,and increase the tolerance of EOC cells to cisplatin.We also found that Exo70 can be degraded through a non-selective autophagolysosome pathway.In sensitive EOC cells,cisplatin induces Exo70 autophagolysosome degradation by affecting phosphorylation of AMPK and mTOR proteins,while in resistant EOC cells,cisplatin induced Exo70 autophagolysosome degradation is blocked.Knockdown or functional inhibition of Exo70 by Endosidin2 can effectively reverse acquired drug resistance of EOC cells.In addition,we further validated the effect of Exo70 on EOC cisplatin resistance in vivo and the possibility that targeting Exo70 can reverse cisplatin resistance.In conclusion,our paper explains the molecular mechanism of Exo70-mediated cisplatin resistance in EOC,and suggests that Endosidin2 can effectively treat acquired resistance in EOC and has the potential for further development.