PPARδ activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis.
PPARδ activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis.
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DOI：
10.1371/journal.pone.0016215
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发表时间：
2011-01-13
期刊：
影响因子：
3.7
通讯作者：
Glazer RI
中科院分区：
文献类型：
--
作者：
Pollock CB;Yin Y;Yuan H;Zeng X;King S;Li X;Kopelovich L;Albanese C;Glazer RI
过氧化物酶体增殖物激活受体δ (PPARδ) 是一种与代谢基因调节和炎症相关的转录因子。它与肿瘤促进和 3-磷酸肌醇依赖性激酶 1 (PDK1) 的调节有关。 PDK1 是 AGC 蛋白激酶家族的关键调节因子，该家族包括与多种恶性肿瘤（包括乳腺癌）有关的原癌基因 AKT/PKB。为了评估 PDK1 在乳腺肿瘤发生中的作用及其与 PPARδ 的相互作用，产生了转基因小鼠，其中 PDK1 在 MMTV 增强子/启动子区域的控制下在乳腺上皮中表达。转基因表达增加了 pT308AKT 和 pS9GSK3β，但没有改变 mTOR、4EBP1、核糖体蛋白 S6 和 PKCα 的磷酸化。转基因乳腺还表达更高水平的 PPARδ，其基因表达谱与食用含有 PPARδ 激动剂 GW501516 的饮食的野生型小鼠相似。用 GW501516 治疗的野生型和转基因小鼠均表现出肿瘤形成速度加快，这在转基因动物中更为明显。 GW501516 治疗伴随着独特的代谢基因表达和代谢组学特征，这在未经治疗的动物中是不存在的。 GW501516 处理的转基因小鼠比处理的野生型小鼠表达更高水平的脂肪酸和磷脂代谢物，表明 PDK1 参与增强 PPARδ 驱动的能量代谢。这些结果表明，PPARδ 激活在肿瘤中引发独特的代谢和代谢组学特征，部分与 PDK1 和 AKT 信号传导相关。
Peroxisome proliferator-activated receptorδ (PPARδ) is a transcription factor that is associated with metabolic gene regulation and inflammation. It has been implicated in tumor promotion and in the regulation of 3-phosphoinositide-dependent kinase-1 (PDK1). PDK1 is a key regulator of the AGC protein kinase family, which includes the proto-oncogene AKT/PKB implicated in several malignancies, including breast cancer. To assess the role of PDK1 in mammary tumorigenesis and its interaction with PPARδ, transgenic mice were generated in which PDK1 was expressed in mammary epithelium under the control of the MMTV enhancer/promoter region. Transgene expression increased pT308AKT and pS9GSK3β, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKCα. The transgenic mammary gland also expressed higher levels of PPARδ and a gene expression profile resembling wild-type mice maintained on a diet containing the PPARδ agonist, GW501516. Both wild-type and transgenic mice treated with GW501516 exhibited accelerated rates of tumor formation that were more pronounced in transgenic animals. GW501516 treatment was accompanied by a distinct metabolic gene expression and metabolomic signature that was not present in untreated animals. GW501516-treated transgenic mice expressed higher levels of fatty acid and phospholipid metabolites than treated wild-type mice, suggesting the involvement of PDK1 in enhancing PPARδ-driven energy metabolism. These results reveal that PPARδ activation elicits a distinct metabolic and metabolomic profile in tumors that is in part related to PDK1 and AKT signaling.