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Repression of NHE1 Expression by PPAR Activation Is a Potential New Approach for Specific Inhibition of the Growth of Tumor Cells In vitro and In vivo

¹ National University Medical Institutes; Departments of ² Physiology, ³ Biochemistry, and ⁴ Pathology, Yong Loo Lin School of Medicine, and ⁵ NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore; ⁶ NUH-NUS Tissue Repository, National University Hospital; ⁷ Duke-NUS Graduate Medical School; ⁸ Singapore-MIT Alliance, Singapore, Singapore

Requests for reprints: Marie-Véronique Clément, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore. Phone: 65-6516-7985; Fax: 65-6779-1453; E-mail: bchmvc{at}nus.edu.sg and Shazib Pervaiz, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore 117597, Singapore. Phone: 65-6516-6602; Fax: 65-6778-8161; E-mail: phssp{at}nus.edu.sg.

Ligand-induced activation of peroxisome proliferator-activated receptor (PPAR) inhibits proliferation in cancer cells in vitro and in vivo; however, the downstream targets remain undefined. We report the identification of a peroxisome proliferator response element in the promoter region of the Na⁺/H⁺ transporter gene NHE1, the overexpression of which has been associated with carcinogenesis. Exposure of breast cancer cells expressing high levels of PPAR to its natural and synthetic agonists resulted in downregulation of NHE1 transcription as well as protein expression. Furthermore, the inhibitory effect of activated PPAR on tumor colony-forming ability was abrogated on overexpression of NHE1, whereas small interfering RNA–mediated gene silencing of NHE1 significantly increased the sensitivity of cancer cells to growth-inhibitory stimuli. Finally, histopathologic analysis of breast cancer biopsies obtained from patients with type II diabetes treated with the synthetic agonist rosiglitazone showed significant repression of NHE1 in the tumor tissue. These data provide evidence for tumor-selective downregulation of NHE1 by activated PPAR in vitro and in pathologic specimens from breast cancer patients and could have potential implications for the judicious use of low doses of PPAR ligands in combination chemotherapy regimens for an effective therapeutic response. [Cancer Res 2009;69(22):8636–44]

Key Words: breast cancer • PPAR • NHE1 • cell growth arrest