HEME-OXYGENASE 1 DRIVES THE METABOLIC FATE IN PROSTATE CANCER

NAVONE NORA; LABANCA ESTEFANIA; VELÁZQUEZ FLORENCIA C.; GUERON GERALDINE; ANSELMINO NICOLAS; VAZQUEZ ELBA S.; CASCARDO FLORENCIA L.; COTIGNOLA JAVIER; LAGE VICKERS SOFIA; ANTICO ARCIUCH VG

Orlando

Congreso; Prostate Cancer: Advances in Basic, Translational, and Clinical Research.; 2017

AACR

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 variationsin a single gene can orchestrate changes in metabolic pathways and confer an adaptiveadvantage. Heme-oxygenase 1 (HO-1) exerts an antitumoral role in PCa inhibiting cellproliferation, migration, tumor growth and angiogenesis. The aim of this work was toassess the role of HO-1 in the metabolic signature of PCa.Through RNA-Seq we found a set of metabolic genes deregulated under pharmacologicalinduction (hemin treatment) or genetic induction of HO-1 in PC3 cells. STAR and ATP5L2were upregulated, while HMGCS2, PRODH and ACOT12 were downregulated. Thesegenes encode for steroid hormone metabolism, ATP synthesis, ketogenesis, proline andlipid metabolism. The analysis of the deregulated genes (2-fold) by Gene Ontologyrevealed alterations in several metabolic pathways such as steroid, proline and lipidmetabolism, and ATP synthesis. Functional analysis highlighted a decrease in oxygenconsumtion rate and ATP production under hemin treatment. Furthermore, HO-1 inductionled to a decrease in the extracellular lactate levels.Bone is the only site of PCa progression, and bone cells are able to produce factors thatfavor progression. However, the molecular nature of this interaction remains elusive. Ourresults performed on co-cultures of PC3 cells (treated or not with hemin) with Raw264.7(pre-osteoclastic) or MC3T3 (pre-osteoblastic) cells demonstrate that HO-1 directs themetabolic fate of bone precursor cells due to the deregulation of glycolytic genes. HO-1induction in PC3 cells downregulated PKM2 and LDHA expression in co-culturedRaw264.7 and MC3T3 cells (p< 0.05).Based on our results, we propose HO-1 as a key regulator of the metabolic status of PCacells and a powerful mediator capable of redefining the metabolic signature of boneprecursor cells, thus, favoring the establishment of a less aggressive phenotype.