Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor γ and mediated by inhibition of translation initiation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001-08, Vol.61 (16), p.6213-6218
• Main Authors: PALAKURTHI, Sangeetha S, AKTAS, Huseyin, GRUBISSICH, Luciano M, MORTENSEN, Richard M, HALPERIN, José A
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Calcium - metabolism; Cell Division - drug effects; Chemotherapy; Cyclin G; Cyclin G1; Cyclins - biosynthesis; Cyclins - metabolism; DNA, Neoplasm - biosynthesis; Eukaryotic Initiation Factor-2 - antagonists & inhibitors; Eukaryotic Initiation Factor-2 - metabolism; Humans; Ligands; Male; Medical sciences; Mice; Mice, Inbred DBA; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Pharmacology. Drug treatments; Phosphorylation - drug effects; Protein Biosynthesis - drug effects; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Cytoplasmic and Nuclear - physiology; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Tumor Cells, Cultured
• ISSN: 0008-5472; 1538-7445

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.