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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Kumar AP,Quake AL,Chang MK,Zhou T,Lim KS,Singh R,Hewitt RE,Salto-Tellez M,Pervaiz S,Clément MVdoi
10.1158/0008-5472.CAN-09-0219subject
Has Abstractpub_date
2009-11-15 00:00:00pages
8636-44issue
22eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-09-0219journal_volume
69pub_type
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