Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands do not potentiate growth of human cancer cell lines

Abstract

Ligands for peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) increase skeletal muscle fatty acid catabolism, improve insulin sensitivity, increase serum high-density lipoprotein cholesterol, elicit anti-inflammatory activity and induce terminal differentiation. Contradictory findings are also reported suggesting that PPARbeta/delta ligands potentiate tumorigenesis by increasing cell proliferation, by inhibiting apoptosis through phosphorylation of Akt and by increasing cyclooxygenase-2 (COX2) and vascular endothelial growth factor (VEGF) expression. The contradictory findings could be due to differences in the model system (cancer cell line versus in vivo), differences in cell culture conditions (with and without serum) or differences in ligands. The present study examined the effect of two different PPARbeta/delta ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS-174T, HepG2 and HuH7) cultured in the presence or absence of serum and compared in vitro analysis with in vivo analysis. Neither PPARbeta/delta ligand increased cell growth or phosphorylation of Akt and no increase in the expression of VEGF or COX2 were detected in any cancer cell line in the presence or absence of serum. Similarly, liver, colon and colon polyps from mice administered these PPARbeta/delta ligands in vivo did not exhibit changes in these markers. Results from these studies demonstrate that serum withdrawal and/or differences in ligands do not underlie the disparity in responses reported in the literature. The quantitative nature of the present findings are inconsistent with the hypothesis that cancer cell lines respond differentially as compared with normal cells, and provide further evidence that PPARbeta/delta ligands do not potentiate tumorigenesis.

High expression of Fatty Acid‐Binding Protein 5 promotes cell growth and metastatic potential of colorectal cancer cells

“…4A,B). This result is consistent with recent studies showing no changes in the expression of PDPK1 and phosphorylation of AKT in response to GW0742 in human HaCaT keratinocytes and CRC cells 38, 39, 40. In addition, the levels of phosphorylated AKT were unchanged by knockdown of FABP5 (Fig.…”

“…Thus, these results strongly suggest that PPAR β/δ does not mediate the pro‐oncogenic activities of FABP5. Indeed, several lines of evidence have shown that PPAR β/δ signaling does not potentiate the growth of human cancer cell lines and attenuates colon carcinogenesis 39, 40, 41, 42. As shown in Fig.…”

Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-β/δ Antagonist GSK3787

“…After this treatment, mRNA was isolated and used for qPCR as described above. It is noteworthy that all of the cell lines have been shown to respond to ligand activation of PPAR␤/␦ and express PPAR␤/␦ mRNA (Hollingshead et al, 2007;Girroir et al, 2008a;He et al, 2008; and data not shown). However, relative expression of PPAR␤/␦ has been noted to be lower in these cancer cell lines compared with normal cells/tissue (data not shown).…”

Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor δ

“…In a genetically modified animal model, intestinal tumorigenesis, but not colon carcinogenesis, was increased in response to GW501516 (Gupta et al, 2004). On the other hand, mice lacking PPAR␦ have an increased predisposition to intestinal tumors (Reed et al, 2004); other reports suggest that ligand activation of PPAR␦ is without effect (Hollingshead et al, 2007) or, in fact, inhibits growth of human cancer cell lines (Bility et al, 2008;Borland et al, 2008) and colon carcinogenesis in mice (Marin et al, 2006). PPAR␦ is a key regulator of skeletal muscle lipid oxidation, and, as outlined in section III, activation of PPAR␦ should have many potential beneficial effects in the context of metabolic disease.…”