title: Targeting mTOR/p70S6K/glycolysis signaling pathway restores glucocorticoid sensitivity to 4E-BP1 null Burkitt Lymphoma.
abstract: BACKGROUND
  Increasing evidence indicates that rapamycin could be used as a potential glucocorticoid (GC) sensitizer in lymphoblastic malignancies via genetic prevention of 4E-BP1 phosphorylation. Interestingly, we found that combined rapamycin with dexamethasone can effectively reverse GC resistance in 4E-BP1 null lymphoma cells. In this study, we investigated the potential link between mTOR/p70S6K signaling pathway, glycolysis, autophagy and GC resistance.
  
  
  METHODS
  Antitumor effects of the combination of rapamycin and dexamethasone were evaluated on cell viability by MTT assay and in vivo studies, on cell cycle and apoptosis by flow cytometry, on autophagy by western blot, MDC staining and transmission electron microscopy and on cell signaling by western blot. Moreover, to test whether inhibiting glycolysis is the core mechanism in rapamycin restoring GC sensitivity, we took glycolysis inhibitor 2-deoxyglucose to replace rapamycin and then evaluated the antitumor effects in vitro.
  
  
  RESULTS
  Raji cells are resistant to rapamycin (IC50 > 1000 nM) or dexamethasone (IC50 > 100 μM) treatment alone. The combination of rapamycin and dexamethasone synergistically inhibited the viability of Raji cells in vitro and in vivo by inducing caspase-dependent and -independent cell death and G0/G1 cell cycle arrest. These effects were achieved by the inhibition of mTOR/p70S6K signaling pathway, which led to the inhibition of glycolysis and the induction of autophagy. Pretreatment with pan-caspase inhibitor z-VAD-fmk or autophagy inhibitor 3-MA failed to protect the cells from combined treatment-induced death. Glycolysis inhibitor combined with dexamethasone produced a similar antitumor effects in vitro.
  
  
  CONCLUSIONS
  Inhibition of mTOR/p70S6K/glycolysis signaling pathway is the key point of therapy in reversing GC resistant in Burkitt lymphoma patients.
authors.affiliation: Laboratory of Hematology/Oncology, Department of Pediatric Hematology/ Oncology, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, 610041, China. guling00@163.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Hematology, West China University Hospital, Sichuan University, Chengdu, 610041, China. lizzie3@sohu.com.
authors.forename: Liping
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Rheumatology, West China University Hospital, Sichuan University, Chengdu, 610041, China. zcsiren@163.com.
authors.forename: Chuan
authors.initials: C
authors.lastname: Zuo
authors.affiliation: Laboratory of Hematology/Oncology, Department of Pediatric Hematology/ Oncology, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, 610041, China. ma_zg@yahoo.com.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Laboratory of Hematology/Oncology, Department of Pediatric Hematology/ Oncology, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, 610041, China. yanlzhang@yeah.net.
authors.forename: Yanle
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Hematology/Oncology, Department of Pediatric Hematology/ Oncology, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, 610041, China. yipingzhu918@qq.com.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Laboratory of Hematology/Oncology, Department of Pediatric Hematology/ Oncology, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, 610041, China. gaoju651220@126.com.
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D003907:Dexamethasone; D003847:Deoxyglucose; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus