Cytochrome 450 metabolites of arachidonic acid promote pheochromocytoma cell growth and tumor associated angiogenesis

COLOMBERO, CECILIA; CARDENAS SOFIA; VENARA MARCELA; MARTIN AYELEN; PENNISI PATRICIA A; BARONTINI MARTA; NOWICKI SUSANA

BIOCHIMIE

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Lugar: Paris; Año: 2020

0300-9084

ESTE TRABAJO HA SIDO ENVIADO PARA SU PUBLICACION. NO HA SIDO PUBLICADO AUN, SOLO SE REGISTRA PARA SU POSIBLE CONSIDERACION PARA LA EVALUACION DE PICT2019 EN CASO DE SER ACEPTADO EN 2020.Abstract: The importance of cytochrome P450 (CYP)-derived arachidonicacid (AA) metabolites, 20-hydroxyeicosatetraenoic acid (20-HETE) andepoxyeicosatrienoic acids (EETs) as tumor growth promotors has alreadybeen described in several cancer types. The aim of this study was toevaluate the role of these compounds in the biology ofpheochromocytoma/paraganglioma. These tumors originate from chromaffincells derived from adrenal medulla (pheochromocytomas) or extra-adrenalautonomic paraganglia (paragangliomas), and they represent the mostcommon hereditary endocrine neoplasia. According to mutations in thedriver genes, these tumors are divided in two clusters: pseudo-hypoxicand kinase-signaling.EETs, but not 20-HETE, exhibited a potent ability to sustain growth in amurine pheochromocytoma cell line (MPC) in vitro, EETs promoted anincrease in cell proliferation and a decrease in cell apoptosis. In amouse model of pheochromocytoma, the inhibition of CYP-mediated AAmetabolism using 1-aminobenzotriazol resulted in slower tumor growth, adecreased vascularization, and a lower final volume. Also, the expressionof AA-metabolizing CYP monooxygenases was detected in tumor samples fromhuman origin, being their apparent abundance and the production of bothmetabolites higher in tumors from the kinase-signaling cluster.This is the first evidence of the importance of CYP- derived AAmetabolites in the biology and development ofpheochromocytoma/paraganglioma tumors.