Abstract A019: Heme-oxygenase 1 drives the metabolic fate in prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Energetic metabolism alterations have become a new hallmark of cancer, since variations in a single gene can orchestrate changes in metabolic pathways and confer an adaptive advantage. Heme-oxygenase 1 (HO-1) exerts an antitumoral role in PCa inhibiting cell proliferation, migration, tumor growth, and angiogenesis. The aim of this work was to assess the role of HO-1 in the metabolic signature of PCa. Through RNA-Seq we found a set of metabolic genes deregulated under pharmacologic induction (hemin treatment) or genetic induction of HO-1 in PC3 cells. STAR and ATP5L2 were upregulated, while HMGCS2, PRODH, and ACOT12 were downregulated. These genes encode for steroid hormone metabolism, ATP synthesis, ketogenesis, proline and lipid metabolism. The analysis of the deregulated genes (2-fold) by Gene Ontology revealed alterations in several metabolic pathways such as steroid, proline and lipid metabolism, and ATP synthesis. Functional analysis highlighted a decrease in oxygen consumption rate and ATP production under hemin treatment. Furthermore, HO-1 induction led to a decrease in the extracellular lactate levels. Bone is the only site of PCa progression, and bone cells are able to produce factors that favor progression. However, the molecular nature of this interaction remains elusive. Our results performed on cocultures of PC3 cells (treated or not with hemin) with Raw264.7 (preosteoclastic) or MC3T3 (preosteoblastic) cells demonstrate that HO-1 directs the metabolic fate of bone precursor cells due to the deregulation of glycolytic genes. HO-1 induction in PC3 cells downregulated PKM2 and LDHA expression in cocultured Raw264.7 and MC3T3 cells (p< 0.05). Based on our results, we propose HO-1 as a key regulator of the metabolic status of PCa cells and a powerful mediator capable of redefining the metabolic signature of bone precursor cells, thus favoring the establishment of a less aggressive phenotype. Citation Format: Valeria G. Antico Arciuch, Florencia Cascardo, Florencia Velazquez, Sofia Lage Vickers, Nicolas Anselmino, Estefania Labanca, Javier Cotignola, Geraldine Gueron, Nora Navone, Elba Vazquez. Heme-oxygenase 1 drives the metabolic fate in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A019.