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Inhibition of esophageal cancer growth through the suppression of PI3K/AKT/mTOR signaling pathway

BACKGROUND: The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is implicated in several cancers. AKT allosteric inhibitor MK2206 and dual PI3K and mTOR inhibitor BEZ235 are promising drug candidates with potential anti-tumor effects.  PURPOSE...

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Detalles Bibliográficos
Autores principales: Shi, Ni, Yu, Hao, Chen, Tong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756275/
https://www.ncbi.nlm.nih.gov/pubmed/31571914
http://dx.doi.org/10.2147/OTT.S205457
Descripción
Sumario:BACKGROUND: The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is implicated in several cancers. AKT allosteric inhibitor MK2206 and dual PI3K and mTOR inhibitor BEZ235 are promising drug candidates with potential anti-tumor effects.  PURPOSE: In this study, we aimed to detect the activation of PI3K/AKT/mTOR pathway and assess the efficacy of MK2206 and BEZ235 in inhibiting esophageal cancer growth. MATERIALS AND METHODS: We used three different systems including carcinogen-induced animal model, human esophageal squamous cell carcinoma (SCC) cell lines, and xenograft mouse model.  RESULTS: Our data indicated that components of the PI3K/AKT/mTOR pathway were overexpressed and activated in esophageal SCC. MK2206 and BEZ235 inhibited cell proliferation, enhanced apoptosis, and induced cell-cycle arrest through downstream effectors SKP2, MCL-1, and cyclin D1 in esophageal SCC cells. MK2206 and BEZ235 also inhibited tumor growth in xenograft mice through the inhibition of AKT phosphorylation. MK2206/BEZ235 combination showed greater anti-tumor effect than MK2206 or BEZ235 alone. The enhanced efficacy of the combination was associated with the inhibition of phosphorylation ATK on both Thr308 and Ser473.  CONCLUSION: The combination of MK2206 and BEZ235 exhibits potent antitumor effects and may have important clinical applications for esophageal SCC treatment.