Involvement of Arachidonic Acid metabolites in Pheochromocytoma biology

COLOMBERO CECILIA EDITH; FERNANDEZ MARÍA CELIA; SANSÓ GABRIELA; VIEITES ANA; BARONTINI MARTA BEATRIZ; PENNISI PATRICIA; NOWICKI SUSANA

San Francisco

Congreso; 95th Annual Meeting & Expo of The Endocrine Society; 2013

The Endocrine Society

Arachidonic acid can be metabolized into 20-hydroxy and epoxide compounds by Cytochrome P450 complex (CYP), CYP4A11 and 4F2 (20-hydroxylases) and CYP 2J2 (epoxygenase). These metabolites have proliferative promoting actions in some normal and cancer cells, among other biological effects. Previous studies have shown an increase in the expression of these isoforms in several types of tumors. Also, a diminished tumoral progression has been observed after their inhibition. Pheochromocytoma and paragangliomas are rare neuroendocrine, catecholamine secreting tumors, associated with a genetic syndrome in about 25% of patients. No data on the role of these CYP- generated metabolites in this kind of tumor is available so far.   The aim of this study was to assess the effect of 20-hydroxylated (20-HETE) and epoxygenated (11,12-EET and 14,15-EET) metabolites in the proliferation rate of Mouse Pheochromocytoma Cells 3 (MPC3) and to analyze the expression 20-hydroxylases and epoxygenases in murine and human pheochromocytoma. CYP expression was analyzed by Western Blot and/or PCR in MPC3 cell culture, murine tumors generated by s.c. injection of MPC3 cells, and frozen human tumor samples of sporadic (n=6) or familial [von Hippel Lindau disease (VHL) (n=5), Multiple Endocrine Neoplasia (MEN 2A) (n=3) or Paraganglioma type 4 (PGL4) (n=2)] pheochromocytomas and paragangliomas. MPC3 cells were incubated with 20-HETE (20uM) or 11,12-EET or 14,15-EET (10nM for both) in low serum medium. 48h incubation resulted in an increase in cell number (increase over control: 20-HETE 64%, n.s.; 11,12-EET 99%, p