PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation
| Autor: | Michael F. Daily, Jonathan Hundley, Roberto Gedaly, Paul Angulo, B. Mark Evers, Changguo Chen |
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| Rok vydání: | 2011 |
| Předmět: |
Sorafenib
MAPK/ERK pathway Niacinamide Carcinoma Hepatocellular MAP Kinase Signaling System Pyridines Morpholines P70-S6 Kinase 1 Antineoplastic Agents mTORC1 Mechanistic Target of Rapamycin Complex 1 mTORC2 Phosphatidylinositol 3-Kinases Cell Line Tumor medicine Humans Furans neoplasms Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Feedback Physiological Sirolimus Antibiotics Antineoplastic Chemistry Triazines Phenylurea Compounds TOR Serine-Threonine Kinases RPTOR Benzenesulfonates Liver Neoplasms Proteins Drug Synergism digestive system diseases Pyrimidines Multiprotein Complexes Cancer research Surgery Proto-Oncogene Proteins c-akt Cell Division medicine.drug Transcription Factors |
| Zdroj: | The Journal of surgical research. 176(2) |
| ISSN: | 1095-8673 |
| Popis: | Background Deregulated Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PKI-587 and sorafenib as single agents or in combination on HCC (Huh7 cell line) proliferation. Materials and Methods 3 H-thymidine incorporation and MTT assay were used to assess Huh7 cell proliferation. Phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways was detected by Western blot. Results We found that PKI-587 is a more potent PI3K/mTOR inhibitor than PI-103. Combination of PKI-587 and sorafenib was a more effective inhibitor of Huh7 proliferation than the combination of PI-103 and sorafenib. Combination of PKI-587 and sorafenib synergistically inhibited epidermal growth factor (EGF)-stimulated Huh7 proliferation compared with monodrug therapy. EGF increased phosphorylation of Ras/Raf downstream signaling proteins MEK and ERK; EGF-stimulated activation was inhibited by sorafenib. However, sorafenib, as a single agent, increased AKT (Ser473) phosphorylation. EGF-stimulated AKT (ser473) activation was inhibited by PKI-587. PKI-587 is a potent inhibitor of AKT (Ser473), mTOR (Ser2448), and S6K (Thr389) phosphorylation; in contrast, rapamycin stimulated mTOR complex 2 substrate AKT(Ser473) phosphorylation although it inhibited mTOR complex 1 substrate S6K phosphorylation. PKI-587, as a single agent, stimulated MEK and ERK phosphorylation. However, when PKI-587 and sorafenib were used in combination, they inhibited all the tested kinases in the Ras/Raf /MAPK and PI3K/AKT/mTOR pathways. Conclusion The combination of PKI-587 and sorafenib has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways. |
| Databáze: | OpenAIRE |
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