ECE2020 Audio ePoster Presentations Pituitary and Neuroendocrinology (217 abstracts)
Antitumor effects of growth hormone-releasing hormone (GHRH) antagonists in ACTH- and GH-secreting pituitary neuroendocrine tumor cell lines
Alessandro Fanciulli 1 , Iacopo Gesmundo 1 , Giacomo Gamba 1 , Villamarin Maria Clara Alvarez 2 , Carlos Dieguez 2 , Chiara Zatelli 3 , Salvatore Cannavò 4 , Silvia Grottoli 1 , Emanuela Arvat 5 , Justo P. Castaño 6 , Raùl M. Luque 6 , Renzhi Cai 7 , Wei Sha 7 , Andrew Victor Schally 8 & Riccarda Granata 1
1University of Turin, Division of Endocrinology, Diabetes and Metabolism, Department of Medical Science, Turin, Italy; 2University of Santiago de Compostela, Centro de Investigaciones Medicas (CIMUS) e Instituto de Investigaciones Sanitarias and Department of Physiology, Santiago de Compostela, Spain; 3University of Ferrara, Section of Endocrinology and Internal Medicine, Department of Medical Sciences, Ferrara, Italy; 4University of Messina, Department of Human Pathology DETEV, Messina, Italy; 5University of Turin, Division of Oncological Endocrinology, Department of Medical Science, Turin, Italy; 6University of Cordoba, Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain; 7University of Miami Miller School of Medicine, Division of Endocrinology, Department of Medicine, Miami, United States; 8University of Miami Miller School of Medicine, Division of Medical Oncology, Department of Medicine, Miami, United States
Pituitary neuroendocrine tumors (PitNETs) are mostly benign lesions originating from the anterior pituitary and represent 10–15% of all the intracranial neoplasms. PitNETscan be classified in non-secretory, clinically non-functioning pituitary adenomas (NFPAs), and secretory, comprising prolactin (PRL), growth hormone (GH) and adrenocoticotropic hormone (ACTH) PitNETs. Surgical resectionis the first line treatment for PitNETs, whereas chemotherapy and radiotherapy are preferred for resistant or metastatic tumors. Growth hormone-releasing hormone (GHRH), apart from promotingpituitary GH secretion, exerts many extrapituitary functions, including stimulation of cell proliferation and survival. GHRH, GHRH receptor (GHRH-R) and splice variant 1 (SV1) of GHRH-R, are expressed in different cancer cell types, where they promote cell proliferation and tumor progression. Conversely, GHRH antagonists inhibit the growth of different tumors in vitro and in vivo; moreover, it has been demonstrated that first generation GHRH antagonists reduce GH secretion in tumoral rat GH-secreting (GH3) cells. However, to date the role of GHRH antagonists in PitNETs remains largely unknown. Thus, we aimed to clarify the role of last generation GHRH antagonists, MIA-602 and MIA-690, on survival, apoptosis and hormone secretion using murine ACTH-secreting PitNETs cells (AtT-20/D16v-F2)and rat PRL- and GH-secreting PitNET cells, transfected with human GHRH-R(GH3-hGHRHR). Our results show that MIA-602 and MIA-690 dose-dependently reduced cell survival and promoted apoptosis in tumoral ACTH-secreting cells and GH3-hGHRHR; in addition, we observed an increase in expression of the proapoptotic protein BAX and the tumorsuppressor protein P53,paralleled by a reduction of the antiapoptotic protein Bcl-2. MIA-602 and MIA-690 also reduced colony formation and expression of c-Myc oncoprotein, indicating inhibitory activity on migration and proliferation. Furthermore, the combination of MIA-602 or MIA-690 with Temozolomide (TMZ), the main chemotherapy agent for PitNETs, produced a synergistic effect on inhibition of cell survival in AtT-20 cells. Finally, both antagonists were able to modulate the secretion of ACTH and GH in AtT20/D16v-F2 and GH3-hGHRHR, respectively. Overall, these results indicate that GHRH antagonists display antitumor activities in ACTH and GH cell lines and suggest their potential use for the treatment of PitNETs, alone or in combination with standard therapies.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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