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PPARδ activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis.

Pollock CB, Yin Y, Yuan H, Zeng X, King S, Li X, Kopelovich L, Albanese C, Glazer RI - PLoS ONE (2011)

Bottom Line: Peroxisome proliferator-activated receptorδ (PPARδ) is a transcription factor that is associated with metabolic gene regulation and inflammation.Transgene expression increased pT308AKT and pS9GSK3β, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKCα.GW501516 treatment was accompanied by a distinct metabolic gene expression and metabolomic signature that was not present in untreated animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.

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.

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The metabolome of GW501516-treated wild-type and MMTV-PDK1 mice.Wild-type (WT) and MMTV-PDK1 (PDK1) mice were maintained for 7 days on either standard or GW501516 (GW)-supplemented diets. The metabolite levels in mammary gland extracts were analyzed by UPLC-ESI-TOFMS. The heatmaps depict the changes in negative ions for control and GW-treated WT and PDK1 mice in 6 replicate analyses.
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pone-0016215-g004: The metabolome of GW501516-treated wild-type and MMTV-PDK1 mice.Wild-type (WT) and MMTV-PDK1 (PDK1) mice were maintained for 7 days on either standard or GW501516 (GW)-supplemented diets. The metabolite levels in mammary gland extracts were analyzed by UPLC-ESI-TOFMS. The heatmaps depict the changes in negative ions for control and GW-treated WT and PDK1 mice in 6 replicate analyses.

Mentions: Metabolomic analysis of the mammary gland revealed similarities and differences between the metabolome of GW501516-treated wild-type and transgenic animals, as well as between control wild-type and transgenic mice. (Figure 4, Table 3, Supporting information Figure S4, Table S3, Table S4, Table S5). The suggestion of increased lipid biosynthesis based on gene array data in GW501516-treated animals was consistent with increased fatty acid and phospholipid levels, and correlated with increased tumorigenesis (Table 3), despite the differences in specific metabolites between the two groups. In contrast, untreated transgenic mice exhibited a reduction in lipid metabolites vs. wild-type mice.


PPARδ activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis.

Pollock CB, Yin Y, Yuan H, Zeng X, King S, Li X, Kopelovich L, Albanese C, Glazer RI - PLoS ONE (2011)

The metabolome of GW501516-treated wild-type and MMTV-PDK1 mice.Wild-type (WT) and MMTV-PDK1 (PDK1) mice were maintained for 7 days on either standard or GW501516 (GW)-supplemented diets. The metabolite levels in mammary gland extracts were analyzed by UPLC-ESI-TOFMS. The heatmaps depict the changes in negative ions for control and GW-treated WT and PDK1 mice in 6 replicate analyses.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3020974&req=5

pone-0016215-g004: The metabolome of GW501516-treated wild-type and MMTV-PDK1 mice.Wild-type (WT) and MMTV-PDK1 (PDK1) mice were maintained for 7 days on either standard or GW501516 (GW)-supplemented diets. The metabolite levels in mammary gland extracts were analyzed by UPLC-ESI-TOFMS. The heatmaps depict the changes in negative ions for control and GW-treated WT and PDK1 mice in 6 replicate analyses.
Mentions: Metabolomic analysis of the mammary gland revealed similarities and differences between the metabolome of GW501516-treated wild-type and transgenic animals, as well as between control wild-type and transgenic mice. (Figure 4, Table 3, Supporting information Figure S4, Table S3, Table S4, Table S5). The suggestion of increased lipid biosynthesis based on gene array data in GW501516-treated animals was consistent with increased fatty acid and phospholipid levels, and correlated with increased tumorigenesis (Table 3), despite the differences in specific metabolites between the two groups. In contrast, untreated transgenic mice exhibited a reduction in lipid metabolites vs. wild-type mice.

Bottom Line: Peroxisome proliferator-activated receptorδ (PPARδ) is a transcription factor that is associated with metabolic gene regulation and inflammation.Transgene expression increased pT308AKT and pS9GSK3β, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKCα.GW501516 treatment was accompanied by a distinct metabolic gene expression and metabolomic signature that was not present in untreated animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.

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.

Show MeSH
Related in: MedlinePlus