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Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-? Pathway.

ABSTRACT: Peroxisome proliferator-activated receptor delta (PPAR-?) is a nuclear receptor transcription factor that regulates gene expression during development and disease states, such as cancer. However, the precise role of PPAR-? during tumorigenesis is not well understood. Recent data suggest that PPAR-? may have context-specific oncogenic and tumor-suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example, in the intestine, pro-obesity diets, such as a high-fat diet (HFD), are associated with increased colorectal cancer incidence. Interestingly, many of the effects of an HFD in the stem and progenitor cell compartment are driven by a robust PPAR-? program and contribute to the early steps of intestinal tumorigenesis. Importantly, the PPAR-? pathway or its downstream mediators may serve as therapeutic intervention points or biomarkers in colon cancer that arise in patients who are obese. Although potent PPAR-? agonists and antagonists exist, their clinical utility may be enhanced by uncovering how PPAR-? mediates tumorigenesis in diverse tissues and cell types as well as in response to diet. Clin Cancer Res; 22(23); 5636-41. ©2016 AACR.

SUBMITTER: Beyaz S

PROVIDER: S-EPMC5135602 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway.

Beyaz Semir S Yilmaz Ömer H ÖH

Clinical cancer research : an official journal of the American Association for Cancer Research 20161004 23

Peroxisome proliferator-activated receptor delta (PPAR-δ) is a nuclear receptor transcription factor that regulates gene expression during development and disease states, such as cancer. However, the precise role of PPAR-δ during tumorigenesis is not well understood. Recent data suggest that PPAR-δ may have context-specific oncogenic and tumor-suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example, in the intestine, pro-obesity diets, such as a ...[more]

PMID: 27702819

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Project description:The transcription factor FoxO1 contributes to the metabolic adaptation to fasting by suppressing muscle oxidation of glucose, sparing it for glucose-dependent tissues. Previously, we reported that FoxO1 activation in C(2)C(12) muscle cells recruits the fatty acid translocase CD36 to the plasma membrane and increases fatty acid uptake and oxidation. This, together with FoxO1 induction of lipoprotein lipase, would promote the reliance on fatty acid utilization characteristic of the fasted muscle. Here, we show that CD36-mediated fatty acid uptake, in turn, up-regulates protein levels and activity of FoxO1 as well as its target PDK4, the negative regulator of glucose oxidation. Increased fatty acid flux or enforced CD36 expression in C(2)C(12) cells is sufficient to induce FoxO1 and PDK4, whereas CD36 knockdown has opposite effects. In vivo, CD36 loss blunts fasting induction of FoxO1 and PDK4 and the associated suppression of glucose oxidation. Importantly, CD36-dependent regulation of FoxO1 is mediated by the nuclear receptor PPARdelta/beta. Loss of PPARdelta/beta phenocopies CD36 deficiency in blunting fasting induction of muscle FoxO1 and PDK4 in vivo. Expression of PPARdelta/beta in C(2)C(12) cells, like that of CD36, robustly induces FoxO1 and suppresses glucose oxidation, whereas co-expression of a dominant negative PPARdelta/beta compromises FoxO1 induction. Finally, several PPRE sites were identified in the FoxO1 promoter, which was responsive to PPARdelta/beta. Agonists of PPARdelta/beta were sufficient to confer responsiveness and transactivate the heterologous FoxO1 promoter but not in the presence of dominant negative PPARdelta/beta. Taken together, our findings suggest that CD36-dependent FA activation of PPARdelta/beta results in the transcriptional regulation of FoxO1 as well as PDK4, recently shown to be a direct PPARdelta/beta target. FoxO1 in turn can regulate CD36, lipoprotein lipase, and PDK4, reinforcing the action of PPARdelta/beta to increase muscle reliance on FA. The findings could have implications in the chronic abnormalities of fatty acid metabolism associated with obesity and diabetes.

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Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-? Pathway.

Publications

Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway.

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