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Abstract
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.
Highlights
Treatment with the selective Peroxisome proliferator-activated receptord (PPARd) agonist GW501516 markedly accelerated mammary carcinogenesis, in mammary tumor virus (MMTV)-PDK1 transgenic mice (PDK1) mice, and the reduction in tumor latency correlated with a metabolic gene expression and metabolomic signature that differed from wild-type animals
These results suggest that the tumor promoting effects of a PPARd agonist are associated in part with PDK1 and a distinct metabolic profile related to glycolysis utilization and lipid biosynthesis
The present study has examined the effect of PDK1 transgene expression on mammary carcinogenesis, and how it impacts the tumor promoting effects of PPARd activation
Summary
3-Phosphoinositide-dependant protein kinase-1 (PDK1) regulates at least 23 members of the AGC protein kinase family, including AKT, p70 ribosomal S6 kinase (S6K) and all isotypes of the protein kinase C (PKC) family [1]. The in vivo consequences of PDK1 transgene expression in the mammary gland, its effect on tumorigenesis, and its influence on the tumor promoting effects of PPARd activation have not been investigated. Treatment with the selective PPARd agonist GW501516 markedly accelerated mammary carcinogenesis, in MMTV-PDK1 mice, and the reduction in tumor latency correlated with a metabolic gene expression and metabolomic signature that differed from wild-type animals. These results suggest that the tumor promoting effects of a PPARd agonist are associated in part with PDK1 and a distinct metabolic profile related to glycolysis utilization and lipid biosynthesis
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