Sanghuh College of Life Sciences, Konkuk University, Seoul, South Korea.
Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston.
Int J Cancer. 2018 Dec 1;143(11):2985-2996. doi: 10.1002/ijc.31864. Epub 2018 Oct 4.
Peroxisome proliferator-activated receptor (PPAR) δ is a promising therapeutic target in metabolic and inflammatory disorders. However, its role in oncogenesis is controversial, and its therapeutic potential remains to be determined. In our study, we show that ligand-activated PPARδ forms a complex with the proto-oncogene product c-Myc. The interaction of PPARδ with c-Myc affected the transcriptional activity of c-Myc and the expression of its target genes. The PPARδ-dependent regulation of c-Myc activity was associated with decreased tumorigenicity in breast cancer cells. Administration of the PPARδ ligand GW501516 inhibited tumor growth in xenograft model mice bearing MDA-MB-231 cells stably expressing wild-type PPARδ, but not those expressing dominant-negative PPARδ, by interfering with c-Myc function through protein-protein interaction. Our results indicating that PPARδ forms an antitumorigenic complex with c-Myc in the presence of ligand suggest a potential role of PPARδ in breast cancer development.
过氧化物酶体增殖物激活受体 (PPAR) δ 是代谢和炎症性疾病有前途的治疗靶点。然而，其在肿瘤发生中的作用存在争议，其治疗潜力仍有待确定。在我们的研究中，我们表明配体激活的 PPARδ 与原癌基因产物 c-Myc 形成复合物。PPARδ 与 c-Myc 的相互作用影响 c-Myc 的转录活性及其靶基因的表达。PPARδ 依赖性的 c-Myc 活性调节与乳腺癌细胞的致瘤性降低有关。PPARδ 配体 GW501516 的给药通过蛋白-蛋白相互作用干扰 c-Myc 功能，抑制稳定表达野生型 PPARδ 的 MDA-MB-231 细胞荷瘤模型小鼠中的肿瘤生长，但不抑制表达显性负性 PPARδ 的肿瘤生长。我们的结果表明，在配体存在的情况下，PPARδ 与 c-Myc 形成一种抗肿瘤复合物，提示 PPARδ 在乳腺癌发生中可能具有作用。
