Abstract
The mammalian target of rapamycin (mTOR) signaling pathway is critical for the growth and proliferation of various malignant tumors, including esophageal squamous cell carcinoma (ESCC). Therefore, targeting of mTOR protein is a promising strategy for therapy in this disease. In the present study, we examined the antitumor effects of a specific mTOR kinase inhibitor, PP242, which blocks both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) pathways, in two ESCC cell lines: Eca-109 and TE-1. We showed that PP242, but not rapamycin, attenuated the activities of both mTORC1 and mTORC2 signaling in ESCC. PP242 inhibited 4E-binding protein-1 phosphorylation and abrogated mTORC1-dependent PI3K/Akt feedback activation. Significantly, PP242 effectively suppressed ESCC cell proliferation, induced apoptosis, and arrested the cell cycle. Furthermore, PP242 promoted cisplatin-induced apoptosis and enhanced the antitumor efficacy of cisplatin in ESCC cells, which was likely to be associated with inhibition of Akt activity. Our results show that simultaneous targeting of both mTORC1 and mTORC2 pathways leads to effective antitumor actions in ESCC, and strongly suggest that dual mTORC1/2 inhibitors should be developed as potential agents for the treatment of ESCC.
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / enzymology
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Carcinoma, Squamous Cell / metabolism
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Cell Cycle / drug effects
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cisplatin / pharmacology*
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Drug Resistance, Neoplasm / drug effects*
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Esophageal Neoplasms / drug therapy*
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Esophageal Neoplasms / enzymology
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Esophageal Neoplasms / metabolism
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Esophageal Squamous Cell Carcinoma
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Feedback, Physiological / drug effects
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Humans
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Indoles / pharmacology
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Molecular Targeted Therapy
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Multiprotein Complexes / antagonists & inhibitors*
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Multiprotein Complexes / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology*
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Protein Processing, Post-Translational / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Purines / pharmacology
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Indoles
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Multiprotein Complexes
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Neoplasm Proteins
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Phosphoproteins
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Protein Kinase Inhibitors
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Purines
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Phosphatidylinositol 3-Kinase
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AKT1 protein, human
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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PP242
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Cisplatin