title: Repression of NHE1 expression by PPARgamma activation is a potential new approach for specific inhibition of the growth of tumor cells in vitro and in vivo.
abstract: Ligand-induced activation of peroxisome proliferator-activated receptor gamma (PPARgamma) 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 PPARgamma to its natural and synthetic agonists resulted in downregulation of NHE1 transcription as well as protein expression. Furthermore, the inhibitory effect of activated PPARgamma 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 PPARgamma in vitro and in pathologic specimens from breast cancer patients and could have potential implications for the judicious use of low doses of PPARgamma ligands in combination chemotherapy regimens for an effective therapeutic response.
authors.affiliation: Departments of Physiology, National University Medical Institutes, Yong Loo Lin School of Medicine, Singapore.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Ai Li
authors.initials: AL
authors.lastname: Quake
authors.forename: Michelle Ker Xing
authors.initials: MK
authors.lastname: Chang
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Kelly Swee Ying
authors.initials: KS
authors.lastname: Lim
authors.forename: Rajeev
authors.initials: R
authors.lastname: Singh
authors.forename: Robert Edwin
authors.initials: RE
authors.lastname: Hewitt
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
authors.forename: Marie-Véronique
authors.initials: MV
authors.lastname: Clément
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007150:Immunohistochemistry; D047495:PPAR gamma / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D045162:Thiazolidinediones / Q000627:therapeutic use; D014162:Transfection
chemical_list: D027682:Cation Transport Proteins; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D045162:Thiazolidinediones; D000077154:Rosiglitazone