title: Combined functional and molecular analysis of tumor cell signaling defines 2 distinct myeloma subgroups: Akt-dependent and Akt-independent multiple myeloma.
abstract: Although the phosphatidylinositide 3-kinase (PI3K)/Akt pathway has been reported to contribute to the malignant growth of multiple myeloma (MM), the true relevance of Akt kinases for this disease is still unclear. In particular, functional analyses in primary tumor cells and genetic target validation experiments are missing. Here, we used combined functional and molecular analyses to determine the importance of Akt activity in a large panel of primary MM samples and in MM cell lines. Akt down-regulation with isoform-specific siRNA constructs or with an Akt1/2-specific pharmacologic inhibitor strongly induced apoptosis in approximately half of the primary MM samples analyzed. Sensitivity to Akt inhibition strongly correlated with the activation status of Akt as determined by immunohistochemistry, phospho-Akt-specific flow cytometry, and Western analysis. Additional blockade of the MAPK and the IL-6R/STAT3 pathways was often not sufficient to decrease the viability of MM cells resilient to Akt inhibition. Taken together, these experiments led to the identification of 2 myeloma subgroups: Akt-dependent and Akt-independent MM.
authors.affiliation: Department of Internal Medicine II, Division of Hematology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Zöllinger
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stühmer
authors.forename: Manik
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
authors.forename: Eugenia
authors.initials: E
authors.lastname: Haralambieva
authors.forename: Hans-Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.forename: Axel
authors.initials: A
authors.lastname: Greiner
authors.forename: Carmen
authors.initials: C
authors.lastname: Wesemeier
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Rath
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
mesh_terms: D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D009101:Multiple Myeloma / Q000145:classification* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
chemical_list: D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt