title: Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma.
abstract: Activation of the phosphatidylinositol 3-kinase (PI(3)K) pathway has been linked with tumour cell growth, survival and resistance to therapy in several cancer types. The active, phosphorylated form of Akt (pAkt) was found to be aberrantly expressed in Hodgkin lymphoma (HL)-derived cell lines and in Hodgkin-Reed-Sternberg (HRS) cells in 27 of 42 (64.3%) of primary lymph node sections of HL, indicative of PI(3)K activity. Akt phosphorylation was not associated with loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression, but with its phosphorylation in HL-cell lines, suggesting that its biological function is impaired. Akt phosphorylation was further induced by CD30 ligand (CD30L), CD40L and receptor activator of nuclear factor kappa B (RANK) ligand. The PI(3)K inhibitor LY294002 demonstrated antiproliferative effects in a dose- and time-dependent manner, which was associated with Akt dephosphorylation on Thr308 and Ser473 sites and dephosphorylation of the downstream ribosomal protein S6. LY209002 induced cell cycle arrest in the G0/G1 phase and apoptosis, which were associated with upregulation of MDM2, downregulation of cyclin D1, activation of caspase 9 and poly-ADP-ribose polymerase cleavage. The Akt inhibitor QLT394 also demonstrated antiproliferative effects in a dose- and time-dependent manner, dephosphorylated ribosomal S6 and cleaved caspase 9. Collectively, these data suggest that the aberrant activation of the PI(3)K/Akt survival pathway in HRS cells is not because of loss of PTEN expression. Our data suggest that PTEN phosphorylation and activation of CD30, CD40 and RANK may play a role in activating Akt in HRS cells.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Georgios V
authors.initials: GV
authors.lastname: Georgakis
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Georgios Z
authors.initials: GZ
authors.lastname: Rassidakis
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
mesh_terms: D015703:Antigens, CD / Q000494:pharmacology; D017209:Apoptosis; D053285:CD30 Ligand; D023201:CD40 Ligand / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016193:G1 Phase; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000037:antagonists & inhibitors*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D048069:Tumor Necrosis Factors / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D053285:CD30 Ligand; D023201:CD40 Ligand; D002352:Carrier Proteins; D053453:Caspase 9; D020169:Caspases; D002867:Chromones; D019938:Cyclin D1; D008562:Membrane Glycoproteins; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D048069:Tumor Necrosis Factors; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505774:TNFSF8 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494929:PTEN protein, human; C506433:CASP9 protein, human