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

ABSTRACT: Peroxisome proliferator-activated receptor? (PPAR?) 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 PPAR?, 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 pS9GSK3?, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKC?. The transgenic mammary gland also expressed higher levels of PPAR? and a gene expression profile resembling wild-type mice maintained on a diet containing the PPAR? 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 PPAR?-driven energy metabolism. These results reveal that PPAR? activation elicits a distinct metabolic and metabolomic profile in tumors that is in part related to PDK1 and AKT signaling.

SUBMITTER: Pollock CB 

PROVIDER: S-EPMC3020974 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature