Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation

// Jonathan D. Diedrich 1,3 , Erandi Rajagurubandara 1 , Mackenzie K. Herroon 1 , Gargi Mahapatra 2 , Maik Huttemann 1,2 and Izabela Podgorski 1,3 1 Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA 2 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA 3 Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA Correspondence to: Izabela Podgorski, email: // Keywords : bone marrow adipocytes, bone metastasis, prostate cancer, glycolysis, Warburg effect Received : August 15, 2016 Accepted : August 21, 2016 Published : August 30, 2016 Abstract Metabolic adaptation is increasingly recognized as a key factor in tumor progression, yet its involvement in metastatic bone disease is not understood. Bone is as an adipocyte-rich organ, and a major site of metastasis from prostate cancer. Bone marrow adipocytes are metabolically active cells capable of shaping tumor metabolism via lipolysis and lipid transfer. In this study, using in vitro and in vivo models of marrow adiposity, we demonstrate that marrow fat cells promote Warburg phenotype in metastatic prostate cancer cells. We show increased expression of glycolytic enzymes, increased lactate production, and decreased mitochondrial oxidative phosphorylation in tumor cells exposed to adipocytes that require paracrine signaling between the two cell types. We also reveal that prostate cancer cells are capable of inducing adipocyte lipolysis as a postulated mechanism of sustenance. We provide evidence that adipocytes drive metabolic reprogramming of tumor cells via oxygen-independent mechanism of HIF-1α activation that can be reversed by HIF-1α downregulation. Importantly, we also demonstrate that the 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.