Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor gamma and mediated by inhibition of translation initiation.
The thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor (PPAR) gamma ligands, known for their ability to induce adipocyte differentiation and increase insulin sensitivity, also exhibits anticancer properties. Currently, TZDs are being tested in clinical trials for treatment of human cancers expressing high levels of PPARgamma because it is assumed that activation of PPARgamma mediates their anticancer activity. Using PPARgamma(-/-) and PPARgamma(+/+) mouse embryonic stem cells, we report here that inhibition of cell proliferation and tumor growth by TZDs is independent of PPARgamma. Our studies demonstrate that these compounds block G(1)-S transition by inhibiting translation initiation. Inhibition of translation initiation is the consequence of partial depletion of intracellular calcium stores and the resulting activation of protein kinase R that phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2), thus rendering eIF2 inactive. PPARgamma-independent inhibition of translation initiation most likely accounts for the anticancer properties of thiazolidinediones.
Palakurthi
S S
SS
Laboratory for Membrane Transport, Harvard Medical School, Boston, Massachusetts 02115, USA.
Aktas
H
H
Grubissich
L M
LM
Mortensen
R M
RM
Halperin
J A
JA
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000096:biosynthesis / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004273:DNA, Neoplasm; D015852:Eukaryotic Initiation Factor-2; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C089946:2,4-thiazolidinedione; D002118:Calcium