The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses.
Interleukin 6 (IL-6) and insulin-like growth factor I (IGF-I) induce proliferative and antiapoptotic responses in multiple myeloma (MM) plasma cells. Because these cytokines may activate the phosphatidylinositol 3-kinase (PI 3-K)/AKT kinase pathway in other cell types, we investigated the role of PI 3-K/AKT in MM cell responses. IGF-I effectively activated PI 3-K in 8226 and OCI-My5 MM cells, but IL-6 was ineffective. However, IL-6 successfully activated PI 3-K in AF-10 MM cells and IL-6-dependent MH.60 plasmacytoma/hybridoma cells. IGF-I also successfully activated PI 3-K in four of four MM patient specimens, and IL-6 activated PI 3-K in three of four specimens. Inhibition of PI 3-K activity with wortmannin or Ly294002 blocked the antiapoptotic effect of IGF-I and the proliferative effect of IL-6 in the myeloma cell lines. Furthermore, a dominant negative PI 3-K construct, expressed in AF-10 cells by adenoviral infection, also significantly inhibited the IL-6 proliferative response in MM cells. In correlation with activation of PI 3-K, IGF-I also effectively activated the AKT kinase in 8226 and OCI-My5 cells, and IL-6 activated AKT in AF-10 and MH.60 cells. However, although incapable of activating PI 3-K in 8226 and OCI-My5 cells, IL-6 successfully activated AKT in these MM lines, suggesting PI 3-K-independent mechanisms of AKT activation. The prevention of a myeloma cell proliferative response resulting from inhibition of PI 3-K activity was not associated with an inhibition of IL-6-dependent extracellular signal-regulated kinase (ERK) activation. These results support a role for the PI 3-K/AKT pathway in cytokine-dependent responses in myeloma cells, which is independent of any activation of the ERK pathway.
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Department of Medicine, West LA VA Medical Center, Los Angeles, California, 90073, USA.
Gardner
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Lichtenstein
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D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010954:Plasmacytoma / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D015850:Interleukin-6; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C494918:AKT1 protein, human