Knockdown of PPAR δ Gene Promotes the Growth of Colon Cancer and Reduces the Sensitivity to Bevacizumab in Nude Mice Model

Abstract

The role of peroxisome proliferator – activated receptor- δ (PPAR δ) gene in colon carcinogenesis remains highly controversial. Here, we established nude mice xenograft model using a human colon cancer cell line KM12C either with PPAR δ silenced or normal. The xenografts in PPAR δ-silenced group grew significantly larger and heavier with less differentiation, promoted cell proliferation, increased expression of vascular endothelial growth factor (VEGF) and similar apoptosis index compared with those of PPAR δ-normal group. After treated with the specific VEGF inhibitor bevacizumab, the capacities of growth and proliferation of xenografts were decreased in both groups while still significantly higher in PPAR δ-silenced group than in PPAR δ-normal group. Administration of PPAR δ agonist significantly decreased VEGF expression in PPAR δ-normal KM12C cells but not in PPAR δ-silenced cells. These findings demonstrate that, knockdown of PPAR δ promotes the growth of colon cancer by inducing less differentiation, accelerating the proliferation and VEGF expression of tumor cells in vivo, and reduces tumor sensitivity to bevacizumab. This study indicates that PPAR δ attenuates colon carcinogenesis.

Establishing the Role of PPARβ/δ in Carcinogenesis

“…Consistent with the notion that relatively higher expression of PPARβ/δ inhibits tumorigenesis, the growth and proliferative indices of a human colon cancer cell line and of ectopic xenografts in immune-compromised mice developing from a derivative of this cell line expressing an RNAi against PPARβ/δ, was markedly increased as compared to controls [20]. This effect may have been due to reduced differentiation and increased expression of vascular endothelial growth factor (VEGF) [20]. These experiments are consistent with studies showing that over-expression of PPARβ/δ and ligand activation of PPARβ/δ markedly inhibited ectopic xenografts using both estrogen receptor (ER)+ and ER− human breast cancer cell lines, in an immune-compromised mouse model [21].…”

“…Consistent with the notion that relatively higher expression of PPARβ/δ inhibits tumorigenesis, the growth and proliferative indices of a human colon cancer cell line and of ectopic xenografts in immune-compromised mice developing from a derivative of this cell line expressing an RNAi against PPARβ/δ, was markedly increased as compared to controls [20]. This effect may have been due to reduced differentiation and increased expression of vascular endothelial growth factor (VEGF) [20].…”

“…Two recent studies suggest that PPARβ/δ agonists can increase expression of VEGF mRNA modestly in cancer cells, but these studies did not measure angiogenic endpoints, and the effects were independent of PPARβ/δ, and therefore likely due to off-target effects of the agonists used (GW501516, L165041) [38, 39]. In contrast, secretion of VEGF was increased in a human colon cancer cell line by knockdown of PPARβ/δ, and ligand activation of PPARβ/δ inhibited secretion of VEGF, an effect that was mitigated by knockdown of PPARβ/δ [20]. Examination of human umbilical vein endothelial cells (HUVEC) cells revealed that L165041 also inhibits VEGF protein expression, tube formation and HUVEC proliferation and migration, and angiogenesis in vivo [40, 41].…”

Low-density lipoprotein docosahexaenoic acid nanoparticles induce ferroptotic cell death in hepatocellular carcinoma

“…Traditionally, PPAR α, γ signaling has been associated with tumor growth suppression 26, 27 , but more recently PPARβ/δ activation has also been reported to promote differentiation and inhibit cancer cell growth. 28, 29 In addition to their tumor suppressive effects, PPARs transcriptional activity is also known to promote lipid oxidation 30 (ie. DHA activation).…”

PPARδ signaling mediates the cytotoxicity of DHA in H9c2 cells

“…In addition, DHA acts as a ligand for PPARs (Gani and Sylte, 2008b). The role of PPARδ in carcinogenesis appears to be the least studied and the most controversial (Peters et al, 2012; Yang et al, 2013). PPARδ is ubiquitously expressed in all adult tissues including the heart (Planavila et al, 2005; Yue et al, 2008).…”