Somatic mutations in peroxisome proliferator-activated receptor-γ are rare events in human cancer cells
Maximilian G. Posch, Chuanbing Zang, Wolf Mueller, Ulrike Lass, Andreas von Deimling, Elena Elstner
Med Sci Monit 2004; 10(8): BR250-254
Available online: 2004-08-01
Background:Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor activated after binding a lipophilic ligand, such as naturally occurring 15dPGJ2. There is striking evidence that PPAR-γ activation leads not only to an increase in insulin sensitivity, but also to tumor cell apoptosis and cell cycle arrest. A growing number of diabetes mellitus II patients currently benefit from treatment with synthetic PPAR-γ agonists, the thiazolidinediones (TZDs), which sensitize peripheral cells towards insulin. Furthermore, some TZDs are undergoing clinical investigations for the treatment of malignant diseases. Therefore, detailed information on the frequency of genetic alterations of PPAR-γ in malignant tumor cells is necessary.Material/Methods: PPAR-γ DNA of 33 histologically different tumor cells was isolated, purified, and all coding regions were separately amplified by PCR. The coding exons were then analyzed by single-stranded conformational polymorphism (SSCP) and bidirectional DNA sequencing.Results: In five breast cancer brain metastasis samples from patients and 28 cancer cell lines derived from lymphoma, glioblastoma, and breast carcinoma we found only one coding region shift in exon 5b of the glioblastoma U373 DNA. This silent mutation does not lead to a change in amino acid alignment. No further polymorphisms, including those which have already been described, could be detected in any other sample.Conclusions: We conclude that somatic mutations in the PPAR gene are exceedingly rare events in malignant tumor cells. This makes PPAR-γ more unlikely to act as a tumor suppressor gene, making it a stable and suitable target for TZD biological cancer therapy.
Keywords: Brain Neoplasms - genetics, Brain Neoplasms - secondary, Breast Neoplasms - genetics, Breast Neoplasms - pathology, DNA Primers, Neoplasms - genetics, Polymorphism, Single-Stranded Conformational, Tumor Cells, Cultured, Brain Neoplasms - secondary, Breast Neoplasms - pathology, DNA Primers, Neoplasms - genetics, Polymorphism, Single-Stranded Conformational, Tumor Cells, Cultured