Synergistic Inhibitory Effects And Molecular Mechanism Of Co-Targeting PLK1 And MTOR In Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma(ESCC)is one of the most frequent malignancies in China with poor prognosis,and at present there is no effective drug available clinically.Overexpression of PLK1(Polo-like kinase 1)and abnormal activation of mTOR(mammalian target of rapamycin)signaling pathways are closely related to the development of a variety of malignant tumors,and there is complicated regulation relationship between PLK1 and mTOR signaling pathways.Previous research results suggest either PLK1 or mTOR signaling pathway is potential therapeutic target of ESCC;however,whether concurrent targeting both of signaling pathways can effectively inhibit the growth of ESCC cells remains to be investigated.In this study,we found that suppression of PLK1 by specific siRNA or inhibitor attenuated mTOR activity in ESCC cells.Phosphorylated S6,a downstream effector of mTOR signaling,was significantly correlated with overexpression of PLK1 in a subset of ESCC.These datas suggest that PLK1 activates mTOR signaling in vitro and in vivo.More importantly,the mTOR inhibitor Rapamycin synergized with PLK1 inhibitor BI 2536 to inhibit ESCC cell proliferation in culture and in mice.Further analysis reveals that PLK1 modulates both mTORCl(mTOR complex 1)and mTORC2(mTOR complex 2)cascades.Therefore,dual inhibition of PLK1 and mTOR yields stronger antitumor effects,at least partially due to synergistic abrogated the activation of S6.4E-BP1(eukaryotic initiation factor 4E-binding protein 1).and AKT by cooperatively blocking mTORC 1 and mTORC2 cascades.These results provide evidence that the mTOR inhibitor Rapamycin synergistically enhances the antitumor effect of PLK1 i1hibitor BI 2536 in ESCC cells.Simultaneous targeting of PLK1 and mTOR may thus be a novel and promising therapeutic strategy for ESCC.