Activation of Peroxisome Proliferator-Activated Receptor δ Stimulates the Proliferation of Human Breast and Prostate Cancer Cell Lines

Abstract

The nuclear receptor peroxisome proliferator-activated receptor ␦ [PPAR␦/␤ (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPAR␦ by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPAR␦ selective agonists. Activation of PPAR␦ with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPAR␦ agonist, GW501516. Conditional expression of PPAR␦ in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPAR␦ in the proliferative response to this drug. Activation of PPAR␦ in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor ␣ (VEGF␣) and its receptor, FLT-1, thus, suggesting that PPAR␦ may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGF␣ and FLT-1 in these cells. Our observations provide the first evidence that activation of PPAR␦ can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPAR␦ antagonists may be of therapeutic value in the treatment of breast and prostate cancer.

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

“…We found by in vitro assay that the growth of intestinal cells was stimulated by the introduction of PPARd cDNA (data not shown, our unpublished data), findings that are consistent with other reports that PPARd enhances the in vitro growth of breast and prostate cancer cells (Stephen et al, 2004). These results suggest that other positive and negative regulators could be simultaneously exerting their effects on cell growth.…”

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

“…Consistent with a PPAR␤/␦-dependent mechanism, we demonstrated that induction of IL-1Ra secretion by rosiglitazone was abolished by transfection with a dominant-negative form of PPAR␤/␦. We showed further that a low concentration of GW-501516, a highly selective PPAR␤/␦ agonist (27,63,64), reproduced the stimulating effect of highdose rosiglitazone on IL-1Ra secretion. Taken together, these data demonstrate that rosiglitazone enhanced IL-1Ra secretion in a PPAR␤/␦-dependent manner and that this likely occurred because its relative affinity for PPAR isotypes was counterbalanced by the pattern of expression of PPAR isotypes in response to IL-1␤ stimulation.…”

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

“…However, there is considerable controversy regarding the safety of PPARβ/δ ligands due to contradictory reports in the literature, in particular those describing effects in cancer models. For example, ligand activation of PPARβ/δ is reported to increase proliferation of human liver, cholangiocarcinoma, breast and prostate cancer cell lines (Stephen et al 2004;Xu et al 2006a;Xu et al 2006b). In contrast, colon cancer cell lines fail to exhibit an increase in cell growth by PPARβ/δ in either the presence or absence of serum (Shimada et al 2002;Stephen et al 2004).…”

“…For example, ligand activation of PPARβ/δ is reported to increase proliferation of human liver, cholangiocarcinoma, breast and prostate cancer cell lines (Stephen et al 2004;Xu et al 2006a;Xu et al 2006b). In contrast, colon cancer cell lines fail to exhibit an increase in cell growth by PPARβ/δ in either the presence or absence of serum (Shimada et al 2002;Stephen et al 2004). Additionally, more recently it was shown that two different PPARβ/δ ligands inhibit cell growth of human liver and colon cancer cell lines, independent of culture medium serum (Hollingshead et al 2007a).…”