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[Cancer Research 61, 6213-6218, August 15, 2001]
© 2001 American Association for Cancer Research

Experimental Therapeutics

Anticancer Effects of Thiazolidinediones Are Independent of Peroxisome Proliferator-activated Receptor {gamma} and Mediated by Inhibition of Translation Initiation1

Sangeetha S. Palakurthi, Huseyin Aktas, Luciano M. Grubissich, Richard M. Mortensen and José A. Halperin2

Laboratory for Membrane Transport, Harvard Medical School, Boston, Massachusetts 02115 [S. S. P., H. A., L. M. G., J. A. H.]; Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115 [H. A., J. A. H.]; and Department of Physiology and Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622 [R. M. M.]

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 PPAR{gamma} because it is assumed that activation of PPAR{gamma} mediates their anticancer activity. Using PPAR{gamma}-/- and PPAR{gamma}+/+ mouse embryonic stem cells, we report here that inhibition of cell proliferation and tumor growth by TZDs is independent of PPAR{gamma}. Our studies demonstrate that these compounds block G1-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. PPAR{gamma}-independent inhibition of translation initiation most likely accounts for the anticancer properties of thiazolidinediones.




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Nuclear Receptors: I. PPARgamma in the gastrointestinal tract: gain or pain?
Am J Physiol Gastrointest Liver Physiol, April 1, 2002; 282(4): G581 - G585.
[Abstract] [Full Text] [PDF]

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R. Cunard, M. Ricote, D. DiCampli, D. C. Archer, D. A. Kahn, C. K. Glass, and C. J. Kelly
Regulation of Cytokine Expression by Ligands of Peroxisome Proliferator Activated Receptors
J. Immunol., March 15, 2002; 168(6): 2795 - 2802.
[Abstract] [Full Text] [PDF]

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N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky
PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis
Circ. Res., April 5, 2002; 90(6): 703 - 710.
[Abstract] [Full Text] [PDF]


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