Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) in Non-Somatotroph Pituitary Tumours and the Effects of PPARα Agonists on MMQ Cells

Michela Anna Polidoro; Sandra Rotondi; Roberta Morace; Liliya Rostomyan; Alessandro Colapietro; Antonietta Arcella; Luca Ventura; Adriano Angelucci; Felice Giangaspero; Vincenzo Esposito; Albert Beckers; Marie-Lise Jaffrain-Rea

doi:10.1055/a-0633-2706

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2018; 50(08): 640-647
DOI: 10.1055/a-0633-2706

Original Article

Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) in Non-Somatotroph Pituitary Tumours and the Effects of PPARα Agonists on MMQ Cells

Authors

Michela Anna Polidoro^*

¹Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
Sandra Rotondi

¹Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
Roberta Morace

²Neuromed Institute, IRCCS, Pozzilli, Italy
Liliya Rostomyan

³Endocrinology, CHU of Liège, University of Liège, Liège, Belgium
Alessandro Colapietro

¹Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
Antonietta Arcella

²Neuromed Institute, IRCCS, Pozzilli, Italy
Luca Ventura

⁴Division of Pathology, “San Salvatore” Hospital, L’Aquila, Italy
Adriano Angelucci

¹Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
Felice Giangaspero

²Neuromed Institute, IRCCS, Pozzilli, Italy

⁵Department of Radiological, Oncological and Anatomopathological Sciences, University “La Sapienza”, Rome, Italy
Vincenzo Esposito

²Neuromed Institute, IRCCS, Pozzilli, Italy

⁶Department of Neurology and Psychiatry, University “La Sapienza”, Rome, Italy
Albert Beckers

³Endocrinology, CHU of Liège, University of Liège, Liège, Belgium
Marie-Lise Jaffrain-Rea

¹Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

²Neuromed Institute, IRCCS, Pozzilli, Italy

Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARα in additional phenotypes of pituitary adenomas (PA), the relationship between PPARα and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARα agonists on lactotroph cells. Seventy-five human PA – 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) – were characterised for PPARα and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARα was expressed in a majority of PA. PPARα immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p=0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p=0.003). PPARα expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100–200 μM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARα is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARα agonists.

Key words

non-functioning pituitary adenomas - prolactinomas - nuclear receptors - aryl hydrocarbon receptor interacting protein (AIP) - fenofibrate - WY 14 643

Volltext

Referenzen

References
1 Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A. High prevalence of pituitary adenomas: A cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 2006; 91: 4769-4775
2 Sumanasekera WK, Tien ES, Turpey R, Vanden Heuvel JP, Perdew GH. Evidence that peroxisome proliferator-activated receptor alpha is complexed with the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2. J Biol Chem 2003; 278: 4467-4473
3 Beckers A, Aaltonen LA, Daly AF, Karhu A. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev 2013; 34: 239-277
4 Rotondi S, Modarelli A, Oliva MA, Rostomyan L, Sanita P, Ventura L, Daly AF, Esposito V, Angelucci A, Arcella A, Giangaspero F, Beckers A, Jaffrain-Rea ML. Expression of Peroxisome Proliferator-Activated Receptor alpha (PPARα) in somatotropinomas: Relationship with Aryl hydrocarbon receptor Interacting Protein (AIP) and in vitro effects of fenofibrate in GH₃ cells. Mol Cell Endocrinol 2016; 426: 61-72
5 König B, Rauer C, Rosenbaum S, Brandsch C, Eder K, Stangl GI. Fasting upregulates PPARalpha target genes in brain and influences pituitary hormone expression in a PPARalpha dependent manner. PPAR Res 2009; 181609
6 Tolón RM, Castillo AI, Aranda A. Activation of the prolactin gene by peroxisome proliferator-activated receptor-alpha appears to be DNA binding-independent. J Biol Chem 1998; 273: 26652-26661
7 Takeda M, Otsuka F, Otani H, Inagaki K, Miyoshi T, Suzuki J, Mimura Y, Ogura T, Makino H. Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LbetaT2 cells. J Endocrinol 2007; 194: 87-99
8 Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res 2005; 51: 85-94
9 Vitale SG, Laganà AS, Nigro A, La rosa VL, Rossetti P, Rapisarda AM, La Vignera S, Corrado F, Buscema M, D’Anna R. Peroxisome Proliferator-Activated Receptor modulation during metabolic diseases and cancers: Master and Minions. PPAR Res 2016; 6517313
10 Derosa G, Sahebkar A, Maffioli P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J Cell Physiol 2018; 233: 153-161
11 Pollinger J, Merk D. Therapeutic applications of the versatile fatty acid mimetic WY14643. Expert Opin Ther Pat 2017; 27: 517-525
12 Heaney AP, Fernando M, Melmed S. PPAR-gamma receptor ligands: Novel therapy for pituitary adenomas. J Clin Invest 2003; 111: 1381-1388
13 Bogazzi F, Ultimieri F, Raggi F, Russo D, Vanacore R, Guida C, Viacava P, Cecchetti D, Acerbi G, Brogioni S, Cosci C, Gasperi M, Bartalena L, Martino E. PPARgamma inhibits GH synthesis and secretion and increases apoptosis of pituitary GH-secreting adenomas. Eur J Endocrinol 2004; 150: 863-875
14 Winczyk K, Pawlikowski M. Immunohistochemical detection of PPARgamma receptors in the human pituitary adenomas: Correlation with PCNA. Folia Histochem Cytobiol 2005; 43: 137-141
15 Pozzi A, Capdevila JH. PPARalpha ligands as antitumorigenic and antiangiogenic agents. PPAR Res 2008; 906542
16 Gao J, Yuan S, Jin J, Shi J, Hou Y. PPARα regulates tumor progression, foe or friend?. Eur J Pharmacol 2015; 15: 560-564
17 Jaffrain-Rea ML, Angelini M, Gargano D. Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: Pathological and clinical implications. Endocr Relat Cancer 2009; 16: 1029-1043
18 Leontiou CA, Gueorguiev M, van der Spuy J, Quinton R, Lolli F, Hassan S, Chahal HS, Igreja SC, Jordan S, Rowe J, Stolbrink M, Christian HC, Wray J, Bishop-Bailey D, Berney DM, Wass JA, Popovic V, Ribeiro-Oliveira Jr A, Gadelha MR, Monson JP, Akker SA, Davis JR, Clayton RN, Yoshimoto K, Iwata T, Matsuno A, Eguchi K, Musat M, Flanagan D, Peters G, Bolger GB, Chapple JP, Frohman LA, Grossman AB, Korbonits M. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metab 2008; 93: 2390-2401
19 Jaffrain-Rea ML, Di Stefano D. Minniti Esposito V, Bultrini A, Ferretti E, Santoro A, Faticanti Scucchi L, Gulino A, Cantore G. A critical reappraisal of MIB-1 labelling index significance in a large series of pituitary tumours: Secreting versus non-secreting adenomas. Endocr Relat Cancer 2002; 9: 103-113
20 Vroonen L, Jaffrain-Rea ML, Petrossians P, Tamagno G, Chanson P, Vilar L, Borson-Chazot F, Naves LA, Brue T, Gatta B, Delemer B, Ciccarelli E, Beck-Peccoz P, Caron P, Daly AF, Beckers A. Prolactinomas resistant to standard doses of cabergoline: A multicenter study of 92 patients. Eur J Endocrinol 2012; 167: 651-662
21 Fratticci A, Grieco FA, Spilioti C, Giangaspero F, Ventura L, Esposito V, Piccirilli M, Santoro A, Gulino A, Cantore G, Alesse E, Jaffrain-Rea ML. Differential expression of neurogenins and NeuroD1 in human pituitary tumors. J Endocrinol 2007; 194: 475-484
22 Greenman Y, Stern N. Non-functioning pituitary adenomas. Best Pract Res Clin Endocrinol Metab 2009; 23: 625-638
23 Nishioka H, Inoshita N, Mete O, Asa SL, Hayashi K, Takeshita A, Fukuhara N, Yamaguchi-Okada M, Takeuchi Y, Yamada S. The complementary role of transcription factors in the accurate diagnosis of clinically nonfunctioning pituitary adenomas. Endocr Pathol 2015; 26: 349-355
24 Caronti B, Palladini G, Calderaro C, Bevilacqua MG, Petrangeli E, Esposito V, Tamburrano G, Gulino A, Jaffrain-Rea ML. Effects of gonadal steroids on the growth of human pituitary adenomas in vitro. Tumour Biol 1995; 16: 353-364
25 Jaffrain-Rea ML, Petrangeli E, Ortolani F, Fraioli B, Lise A, Esposito V, Spagnoli LG, Tamburrano G, Frati L, Gulino A. Cellular receptors for sex steroids in human pituitary adenomas. J Endocrinol 1996; 151: 175-184
26 Colao A, Savastano S. Medical treatment of prolactinomas. Nat Rev Endocrinol 2011; 7: 267-278
27 Blanquart C, Mansouri R, Fruchart JC, Staels B, Glineur C. Different ways to regulate the PPARalpha stability. Biochem Biophys Res Commun 2004; 319: 663-670
28 Wadosky KM, Willis MS. The story so far: Post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation. Am J Physiol Heart Circ Physiol 2012; 302: H515-H526
29 Hirotani M, Tsukamoto T, Bourdeaux J, Sadano H, Osumi T. Stabilization of peroxisome proliferator-activated receptor alpha by the ligand. Biochem Biophys Res Commun 2001; 288: 106-110
30 Hibberts NA, Simpson DJ, Bicknell JE, Broome JC, Hoban PR, Clayton RN, Farrell WE. Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic human pituitary tumors. Clin Cancer Res 1999; 5: 2133-2139
31 Karavitaki N, Collison K, Halliday J, Byrne JV, Price P, Cudip S, Wass JA. What is the natural history of nonoperated nonfunctioning pituitary adenomas. Clin Endocrinol (Oxf) 2007; 67: 938-943
32 Øystese KA, Evang JA, Bollerslev J. Non-functioning pituitary adenomas: Growth and aggressiveness. Endocrine 2016; 53: 28-34
33 Featherstone K, White MR, David JS. The prolactin gene: A paradigm of tissue-specific gene regulation with complex temporal transcription dynamics. J Neuroendocrinol. 2012; 24: 977-990
34 Bernardes A, Souza PC, Muniz JR, Ricci CG, Ayers SD, Parekh NM, Godoy AS, Trivella DB, Reinach P, Webb P, Skaf MS, Polikarpov I. Molecular mechanism of peroxisome proliferator-activated receptor α activation by WY14643: A new mode of ligand recognition and receptor stabilization. J Mol Biol 2013; 425: 2878-2893
35 Shimomura K, Ikeda M, Ariyama Y, Proks P, Shimomura Y, Mori M, Matsumoto S. Effect of peroxisome proliferator-activated receptor alpha ligand fenofibrate on K(v) channels in the insulin-secreting cell line HIT-T15. Gen Physiol Biophys 2006; 25: 455-460
36 Gonzalez-Iglesias AE, Murano T, Li S, Tomić M, Stojilkovic SS. Dopamine inhibits basal Prolactin release in pituitary lactotrophs through pertussis toxin-sensitive and -insensitive signaling pathways. Endocrinology 2008; 149: 1470-1479
37 Merk D, Zettl M, Steinhilber D, Werz O, Schubert-Zsilavecz M. Pirinixic acids: Flexible fatty acid mimetics with various biological activities. Future Med Chem 2015; 7: 1597-1616
38 Pyper SR, Viswakarma N, Yu S, Reddy JK. PPARalpha: Energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal 2010; 8: e002
39 Lakshmi SP, Reddy AT, Banno A, Reddy RC. PPAR agonists for the prevention and treatment of lung cancer. PPAR Res 2017; 8252796
40 Esmaeili MA, Yadav S, Gupta RK, Waggoner GR, Deloach A, Calingasan NY, Beal MF, Kiaei M. Preferential PPAR-α activation reduces neuroinflammation, and blocks neurodegeneration in vivo. Hum Mol Genet 2016; 25: 317-332

Zusatzmaterial

Supplementary Material (PDF)