Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses.
IL-6 is an established growth factor for multiple myeloma tumor cells, stimulating proliferative and survival responses. Recent work indicates that IL-6 can activate the AKT kinase in myeloma cells. Thus, to test a potential role for AKT in IL-6-induced cellular responses, we transfected myeloma cell lines with an active 'E40K' or dominant negative'PH AKT construct using an adenoviral vector. Transfection of the E40K into myeloma cells resulted in enhanced tumor cell growth and expression of the PH dominant negative AKT resulted in both inhibition of the IL-6-dependent proliferative response and a decrease in S phase distribution. While transfection of E40K protected myeloma cells from dexamethasone-induced apoptosis, the dominant negative PH had no effect on the ability of IL-6 to protect these cells from dexamethasone. These results clearly demonstrate that AKT activation is critical for the IL-6 proliferative response. In addition, although the level of AKT activation can regulate sensitivity to dexamethasone-induced apoptosis, additional cytokine-induced AKT-independent pathways can mediate IL-6 protection against dexamethasone. DOI: 10.1038/sj/onc/1205194
Hsu
Jung-hsin
JH
Department of Medicine and Pathology, West LA VA-UCLA Medical Center and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, CA 90073, USA.
Shi
Yijiang
Y
Hu
Liping
L
Fisher
Myrna
M
Franke
Thomas F
TF
Lichtenstein
Alan
A
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D005434:Flow Cytometry; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D016207:Cytokines; D003907:Dexamethasone; D015850:Interleukin-6; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D000077191:Wortmannin; C494918:AKT1 protein, human