Growth control of multiple myeloma cells through inhibition of glycogen synthase kinase-3.
Anti-apoptotic pathways play a central role in the survival of multiple myeloma cells. The contribution of PI3-kinase and Akt kinase in mediating myeloma cell survival is well established although the role of glycogen synthase kinase-3 (GSK3) is less defined. In this study we determined the contribution of GSK3 in growth regulation of myeloma cells. We treated six different multiple myeloma cell lines with a Thiadiazolidinone (TDZD), a non-competitive inhibitor of GSK3 and determined its effects on proliferation and apoptosis. In addition we determined the activation of forkhead transcription factors (FOXO) in response to TDZD. TDZD inhibited proliferation and induced apoptosis of all myeloma cell lines. TDZD was also effective in inducing apoptosis of primary myeloma cells whereas CD34 positive normal hematopoietic cells were protected from apoptosis. Furthermore, TDZD-mediated inhibition of GSK3 resulted in dephosphorylation and activation of FOXO3a. In primary myeloma cells FOXO transcription factors were highly phosphorylated where as the levels of GSK3 phosphorylation was quite low. The levels of the pro-apoptotic proteins Fas ligand (FasL) and IkappaBalpha increased after treatment with TDZD in myeloma cell lines. These studies provide the basis for further testing of GSK3 inhibitors in the clinical setting.
Zhou
Ying
Y
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Uddin
Shahab
S
Zimmerman
Todd
T
Kang
Jeong-Ah
JA
Ulaszek
Jodie
J
Wickrema
Amittha
A
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000032:analysis; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D020672:I-kappa B Proteins / Q000032:analysis; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D000072000:NF-KappaB Inhibitor alpha; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; C499517:FOXO3 protein, human; D053222:Fas Ligand Protein; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; D000072000:NF-KappaB Inhibitor alpha; D038362:Glycogen Synthase Kinase 3