Although cancer cells have traditionally been thought to rely on the glycolytic pathway to generate ATP, recent studies suggest that cancer cells can shift to the fatty acid oxidation pathway as an alternative energy source. All of the factors that induce and regulate this adaptive shift in metabolism are not known. Cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) is produced at high levels in colon cancer, and multiple lines of evidence from human-, animal-, and cell line-based studies indicate that PGE(2) plays a pro-oncogenic role in colorectal cancer progression. We have shown previously that exposure of colon cancer cells to PGE(2) promotes cell survival, in part by inducing the expression of the nuclear orphan receptor NR4A2. Here, we report that PGE(2)-induced NR4A2 increased fatty acid oxidation by inducing the expression of multiple proteins in the fatty acid oxidation pathway. NR4A2 was found to bind directly to Nur77-binding response elements located within the regulatory region of these genes. Nur77-binding response element binding also resulted in the recruitment of transcriptional coactivators and induction of gene expression. Collectively, our findings suggest that NR4A2 plays a key role as a transcriptional integration point between the eicosanoid and fatty acid metabolic pathways. Thus, PGE(2) is a potential regulator of the adaptive shift to energy utilization via fatty acid oxidation that has been observed in several types of cancer.