gw-7845 and Colorectal-Neoplasms

Peroxisome proliferator-activated receptor γ (PPARγ) may serve as a useful target for drug development in non-diabetic diseases. However, some colorectal cancer cells are resistant to PPARγ agonists by mechanisms that are poorly understood. Here, we provide the first evidence that elevated PPARδ expression and/or activation of PPARδ antagonize the ability of PPARγ to induce colorectal carcinoma cell death. More importantly, the opposing effects of PPARδ and PPARγ in regulating programmed cell death are mediated by survivin and caspase-3. We found that activation of PPARγ results in decreased survivin expression and increased caspase-3 activity, whereas activation of PPARδ counteracts these effects. Our findings suggest that PPARδ and PPARγ coordinately regulate cancer cell fate by controlling the balance between the cell death and survival and demonstrate that inhibition of PPARδ can reprogram PPARγ ligand-resistant cells to respond to PPARγ agonists.

Topics: Apoptosis; Caspase 3; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; DNA Fragmentation; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Humans; Inhibitor of Apoptosis Proteins; Oxazoles; PPAR delta; PPAR gamma; Survivin; Thiazoles; Tyrosine

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have been demonstrated to exert an inhibitory effect on cell growth, and to induce the cell differentiation and apoptosis of colorectal cancer cells. PPARgamma was therefore proposed as a therapeutic target. Recently, a variant of PPARgamma which functions as a dominant negative (ORF4) was described. Expression of this protein may prevent PPARgamma ligand efficiency in colon cancer treatment. In an effort to evaluate the importance of this variant, we determined the expression level of PPARgamma and that of the splicing variant ORF4 in a series of 28 human colon adenocarcinomas relative to paired normal mucosa by real-time PCR. PPARgamma expression was found to be heterogeneous among tumors. ORF4 was also expressed, but represented <10% of the PPARgamma transcripts. This low level was also found in several human colon cancer cell lines treated or not with a specific PPARgamma ligand in preparations of isolated human colonic epithelial cells and in mouse colon. We conclude that ORF4 expression is a general phenomenon, and that its low level should not affect the efficiency of selective PPARgamma modulators in colon cancer treatment.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Alternative Splicing; Caco-2 Cells; Cell Line, Tumor; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Male; Middle Aged; Oxazoles; PPAR gamma; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tyrosine