This phenomenon, termed pseudohypoxia, is thought to facilitate adaptation of tumor cells to harsh conditions and to promote survival and resistance to therapy [47-49]. also reveal that prostate malignancy cells are capable of inducing adipocyte lipolysis as a postulated mechanism of sustenance. We provide evidence that adipocytes drive metabolic reprogramming of tumor cells oxygen-independent mechanism of HIF-1 activation that can be reversed by HIF-1 Imatinib (Gleevec) downregulation. Importantly, we also demonstrate that this observed metabolic signature in tumor cells exposed to adipocytes mimics the expression patterns seen in patients with metastatic disease. Together, our data provide evidence for a functional relationship between marrow adipocytes and tumor cells in bone that has likely implications for tumor growth and survival within the metastatic niche. lipid synthesis and alterations in fatty acid catabolism and steroidogenesis pathways are now emerging as important mechanisms linking dysregulated lipid metabolism in the primary prostate tumor with subsequent progression and reduced survival [7, 12, 13]. In contrast to the primary disease, however, the metabolic phenotype of metastatic prostate cancers is not well-understood. The acquisition of a glycolytic phenotype in advanced stages of prostate malignancy has been suggested by the reports of increased accumulation of fluorodeoxyglucose (FDG)  and the immunohistochemical evidence of expression of glycolytic markers and monocarboxylate transporters . The mechanisms contributing to metabolic adaptation and progression of metastatic prostate tumors in bone has not, however, been previously explored and are not known. Metastatic growth in bone is a complex process including reciprocal interactions between the tumor cells and the host bone microenvironment. One of the most abundant, yet overlooked components of the metastatic marrow niche are the bone marrow adipocytes [16-18]. Adipocyte figures in the marrow increase with age, obesity and metabolic disorders [18-23], all of which are also risk factors for metastatic disease [24-28]. We as well as others have shown previously that marrow excess fat cells, as highly metabolically active cells, can serve as a source of lipids for malignancy cells, and promote growth, invasion, Imatinib (Gleevec) and aggressiveness of metastatic tumors in bone [16, 29, 30]. Based on the growing evidence from cancers that grow in adipocyte-rich tissues, it is becoming apparent that one of the ways adipocytes can affect tumor cell behavior is usually through modulation of malignancy cell metabolism . Although direct effects of adipocyte-supplied lipids on tumor metabolism have not been investigated in the context of metastatic prostate malignancy, there have been studies in other cancers demonstrating that some lipids do have the ability to enhance the Warburg Effect in tumor cells [32-36]. Reciprocally, tumor cells have been shown to act as metabolic parasites by inducing lipolysis in adipocytes [37, 38]. This is important in the regulation of tumor metabolism as the lipolysis-generated glycerol can feed into the glycolytic pathway [39-41] and the released fatty acids can be oxidized through -oxidation [42, 43]. As active and vital components of the bone-tumor microenvironment, adipocytes are likely to be involved in the metabolic adaptation of tumors in the metastatic niche; however, the concept of metabolic coupling between marrow adipocytes and tumor cells leading to metabolic reprogramming in the tumor has not been explored before. One of the principal mechanisms Imatinib (Gleevec) behind metabolic reprogramming is usually hypoxic stress and activation of hypoxia inducible factor (HIF) . HIF-1 stimulates the conversion of glucose to pyruvate and lactate by upregulating important enzymes involved in glucose transport, glycolysis, and lactate extrusion, and by decreasing conversion of pyruvate to acetyl-CoA through transactivation of pyruvate dehydrogenase kinase (PDK1) and subsequent inhibition of pyruvate dehydrogenase (PDH) . Regulation of lactate dehydrogenase (LDHa) and PDK1 by HIF-1 maintains the pyruvate away from mitochondria, thus depressing mitochondrial respiration . Under normoxic conditions, HIF-1 is usually rapidly degraded by the ubiquitin-proteasome pathway . Decreased oxygen availability prevents HIF-1 hydroxylation leading to its stabilization and activation of downstream pathways . In malignancy cells, HIF-1 stabilization and activation can occur during normoxia multiple oxygen-independent pathways . This phenomenon, termed pseudohypoxia, is usually Mouse monoclonal to FYN thought to facilitate adaptation of tumor cells to harsh conditions and to promote survival and resistance to therapy [47-49]. Whether HIF-1-dependent signaling plays a role in metabolic reprogramming of prostate tumor cells in bone is not known. The objective of this study was to elucidate the role of bone marrow adiposity in the modulation of tumor metabolism and adaptation within the bone microenvironment. Using models of diet-induced marrow adiposity in combination with models of paracrine, autocrine, and endocrine signaling between bone marrow adipocytes and prostate malignancy cells, we show that bone marrow adipocytes are responsible for enhancing the glycolytic phenotype of metastatic prostate malignancy cells. We demonstrate that bidirectional conversation between adipocytes and tumor cells prospects to increased expression of glycolytic enzymes, increased lactate production, and decreased mitochondrial oxidative phosphorylation in tumor cells necessary malignancy cell-initiated paracrine crosstalk. We also reveal that this observed metabolic signature in tumor cells exposed to adipocytes mimics the expression patterns seen in Imatinib (Gleevec) patients with metastatic disease. These results offer potential.