Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

Abstract

The development of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands for the treatment of diseases including metabolic syndrome, diabetes and obesity has been hampered due to contradictory findings on their potential safety. For example, while some reports show that ligand activation of PPARβ/δ promotes the induction of terminal differentiation and inhibition of cell growth, other reports suggest that PPARβ/δ ligands potentiate tumorigenesis by increasing cell proliferation. Some of the contradictory findings could be due in part to differences in the ligand examined, the presence or absence of serum in cell cultures, differences in cell lines, or differences in the method used to quantify cell growth. For these reasons, this study examined the effect of ligand activation of PPARβ/δ on cell growth of two human cancer cell lines, MCF7 (breast cancer) and UACC903 (melanoma) in the presence or absence of serum using two highly specific PPARβ/δ ligands, GW0742 or GW501516. Culturing cells in the presence of either GW0742 or GW501516 caused upregulation of the known PPARβ/δ target gene angiopoetin-like protein 4 (ANGPTL4). Inhibition of cell growth was observed in both cell lines cultured in the presence of either GW0742 or GW501516, and the presence or absence of serum had little influence on this inhibition. Results from the present studies demonstrate that ligand activation of PPARβ/δ inhibits the growth of both MCF7 and UACC903 cell lines and provide further evidence that PPARβ/δ ligands are not mitogenic in human cancer cell lines.

Expression of angiopoietin-like 4 in human gastric cancer: ANGPTL4 promotes venous invasion

“…Prognostic investigation showed specifically that 7 cases without ANGPTL4 in 13 patients of cancer related-death showed local recurrence (Table III). Some reports indicated that ANGPTL4 regulates the cell motility and invasiveness (20,21). These findings suggest that the carcinoma with ANGPTL4 is more susceptible to distant metastasis and the carcinoma without ANGPTL4 shows a tendency for stromal invasion.…”

“…cancer (20), hepatocellular carcinoma (39), prostate cancer (40) and melanoma (21). Angiopoietin family members usually regulate the differentiation or invasion of cancer cells through the activation of its receptor Tie-2 and downstream tyrosine kinase pathway (8,9,41).…”

“…Secretion of ANGPTL4 enables tumour cells to extravasate into other tissue and to seed micrometastases. However, it has been also reported that ANGPTL4 prevents the metastatic process by inhibiting vascular activity as well as tumour cell motility and invasiveness (20,21). The effects of ANGPTL4 in experimental systems are still unclear in tumour biology.…”

Emerging Roles of Angiopoietin-like 4 in Human Cancer

“…This finding further implicates ANGPTL4 in cancer progression, although evidence that PPARs upregulate ANGPTL4 directly in tumor cells is still lacking. Girroir and colleagues suggested that PPARb/d modulates ANGPTL4 expression during tumorigenesis in human breast cancer and melanoma cell lines, although Zhu and colleagues reported no apparent correlation between the expression of PPARs and ANGPTL4 in SCC (11,26). A recent study suggested that prostaglandin E2 (PGE 2 ) may transactivate PPARb/d to regulate the expression of ANGPTL4 under hypoxic conditions (25).…”

Effects of a methanolic fraction of soybean seeds on the transcriptional activity of peroxisome proliferator-activated receptors (PPAR)

“…However, little is known about the possibility that isoflavones activate PPARβ/ δ, which plays a critical role in the regulation of metabolic homeostasis, and also in cardiac lipid metabolism (15,16), fetal development (17), inhibition of human cancer cell line growth (18), protection against liver toxicity (19), modulation of inflammation (6,20), and improved skeletal muscle oxidative enzyme activity in obese patients with type 2 diabetes mellitus (21).…”