title: Rapamycin Enhances the Anti-Cancer Effect of Dasatinib by Suppressing Src/PI3K/mTOR Pathway in NSCLC Cells.
abstract: Src and the mammalian target of rapamycin (mTOR) signaling are commonly activated in non-small cell lung cancer (NSCLC) and hence potential targets for chemotherapy. Although the combined use of Src inhibitor Dasatinib with other chemotherapeutic agents has shown superior efficacy for cancer treatment, the mechanisms that lead to enhanced sensitivity of Dasatinib are not completely understood. In this study, we found that Rapamycin dramatically enhanced Dasatinib-induced cell growth inhibition and cell cycle G1 arrest in human lung adenocarcinoma A549 cells without affecting apoptosis. The synergistic effects were consistently correlated with the up-regulation of cyclin-dependent kinases inhibitor proteins, including p16, p19, p21, and p27, as well as the repression of Cdk4 expression and nuclear translocation. Mechanistic investigations demonstrated that FoxO1/FoxO3a and p70S6K/4E-BP1, the molecules at downstream of Src-PI3K-Akt and mTOR signaling, were significantly suppressed by the combined use of Dasatinib and Rapamycin. Restraining Src and mTOR with small interfering RNA in A549 cells further confirmed that the Src/PI3K/mTOR Pathway played a crucial role in enhancing the anticancer effect of Dasatinib. In addition, this finding was also validated by a series of assays using another two NSCLC cell lines, NCI-H1706 and NCI-H460. Conclusively, our results suggested that the combinatory application of Src and mTOR inhibitors might be a promising therapeutic strategy for NSCLC treatment.
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, China; School of Medicine Cancer Institute, Tongji University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, China; School of Medicine Cancer Institute, Tongji University, Shanghai, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, China; School of Medicine Cancer Institute, Tongji University, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, China; School of Medicine Cancer Institute, Tongji University, Shanghai, China.
authors.forename: Heyong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, China; School of Medicine Cancer Institute, Tongji University, Shanghai, China.
authors.forename: Songwen
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015290:Second Messenger Systems / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051358:Cyclin-Dependent Kinase 4; D000069439:Dasatinib; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D019061:src-Family Kinases; C495900:CDK4 protein, human