The interleukin-6 (IL-6) signaling pathway contributes to myeloma cell growth and viability through activation of the PI3/Akt kinase pathway. To understand the downstream signaling elements in the PI3/Akt kinase pathway that are involved in the regulation of myeloma cell growth, we determined the role played by glycogen synthase kinase 3 (Gsk3) and forkhead transcription factors (FH) in the RPM1-8226 myeloma cell line. We demonstrate that both Gsk3 and FH transcription factors FKHRL1 (FOX3a), FKHR (FOXO1a), and AFX (FOXO4) are phosphorylated (inactivated) by IL-6. Further, we show that inhibitors of Gsk3 induce dephosphorylation of FKHRL1 and FKHR at their threonine sites and upregulate the cyclin-dependent kinase inhibitor p27(kipl). Finally, we show that inhibition of Gsk3 activity is sufficient to suppress cell growth and induce apoptosis thus overriding the effects of IL-6 in myeloma cells. (C) 2002 Elsevier Science (USA). All rights reserved.