title: Synergism of PI3K/Akt inhibition and Fas activation on colon cancer cell death.
abstract: Fas and PI3K/Akt signaling pathways pivotally impact on cancer cell death and survival respectively and are considered as promising targets for innovative anticancer therapies. To better characterize the combination effect of PI3K/Akt inhibitors and Fas agonists and understand the profile of the interaction between PI3K/Akt and Fas signaling, we qualitatively and quantitatively evaluated the combination effect of PI3K/Akt inhibitors LY294002, Akt inhibitor VIII and FasL. At the concentration that can block cell cycle progression and DNA synthesis but not elicit apoptosis, these inhibitors potentiate FasL to induce apoptosis. At higher concentrations, when the PI3K/Akt inhibitors induce apoptosis, they synergize FasL to induce apoptosis. In addition, PI3K/Akt inhibition significantly facilitates the Fas-mediated apoptotic signaling. Understanding the combination effects between PI3K/Akt inhibition and Fas activation not only leads to rational design of effective combination therapy of PI3K/Akt inhibitors but also improve our knowledge about the impact of PI3K-Akt pathway on Fas signaling and the potential modulation of innate immune system by PI3K-Akt-targeting drugs in anticancer treatment.
authors.affiliation: Université de Nice, Institut de Biologie Valrose, CNRS UMR 7277, INSERM UMR 1091, Nice, France.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Université de Nice, Institut de Biologie Valrose, CNRS UMR 7277, INSERM UMR 1091, Nice, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Derijard
authors.affiliation: Université de Nice, Institut de Biologie Valrose, CNRS UMR 7277, INSERM UMR 1091, Nice, France.
authors.forename: Krittalak
authors.initials: K
authors.lastname: Chakrabandhu
authors.affiliation: Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Bing-Shun
authors.initials: BS
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Université de Nice, Institut de Biologie Valrose, CNRS UMR 7277, INSERM UMR 1091, Nice, France. Electronic address: hueber@unice.fr.
authors.forename: Anne-Odile
authors.initials: AO
authors.lastname: Hueber
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004357:Drug Synergism; D053222:Fas Ligand Protein / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D002867:Chromones; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D019014:fas Receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Apoptosis; Fas; PI3K; Synergism