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 rece ptor (PPAR) gamma ligands, known for their ability to induce adipocyte diff erentiation and increase insulin sensitivity, also exhibits anticancer prop erties. Currently, TZDs are being tested in clinical trials for treatment o f human cancers expressing high levels of PPAR gamma because it is assumed that activation of PPAR gamma mediates their anticancer activity. Using PPA R gamma (-/-) and PPAR gamma (+/+) mouse embryonic stem cells, we report he re that inhibition of cell proliferation and tumor growth by TZDs is indepe ndent of PPAR gamma. Our studies demonstrate that these compounds block G(1 )-S transition by inhibiting translation initiation. Inhibition of translat ion initiation is the consequence of partial depletion of intracellular cal cium stores and the resulting activation of protein kinase R that phosphory lates the alpha subunit of eukaryotic initiation factor 2 (eIF2), thus rend ering eIF2 inactive. PPAR gamma -independent inhibition of translation init iation most likely accounts for the anticancer properties of thiazolidinedi ones.