Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling
Pituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticanc...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/16/3950 |
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| author | Iacopo Gesmundo Giuseppina Granato Antonio C. Fuentes-Fayos Clara V. Alvarez Carlos Dieguez Maria Chiara Zatelli Noemi Congiusta Dana Banfi Nunzia Prencipe Sheila Leone Luigi Brunetti Justo P. Castaño Raúl M. Luque Renzhi Cai Wei Sha Ezio Ghigo Andrew V. Schally Riccarda Granata |
| author_facet | Iacopo Gesmundo Giuseppina Granato Antonio C. Fuentes-Fayos Clara V. Alvarez Carlos Dieguez Maria Chiara Zatelli Noemi Congiusta Dana Banfi Nunzia Prencipe Sheila Leone Luigi Brunetti Justo P. Castaño Raúl M. Luque Renzhi Cai Wei Sha Ezio Ghigo Andrew V. Schally Riccarda Granata |
| author_sort | Iacopo Gesmundo |
| collection | DOAJ |
| description | Pituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticancer effects, and early GHRH antagonists were found to inhibit GHRH-induced secretion of pituitary GH in vitro and in vivo. However, the antitumor role of GHRH antagonists in PAs is largely unknown. Here, we show that the GHRH antagonists of MIAMI class, MIA-602 and MIA-690, inhibited cell viability and growth and promoted apoptosis in GH/prolactin-secreting GH3 PA cells transfected with human GHRH receptor (GH3-GHRHR), and in adrenocorticotropic hormone ACTH-secreting AtT20 PA cells. GHRH antagonists also reduced the expression of proteins involved in tumorigenesis and cancer progression, upregulated proapoptotic molecules, and lowered GHRH receptor levels. The combination of MIA-690 with temozolomide synergistically blunted the viability of GH3-GHRHR and AtT20 cells. Moreover, MIA-690 reduced both basal and GHRH-induced secretion of GH and intracellular cAMP levels. Finally, GHRH antagonists inhibited cell viability in human primary GH- and ACTH-PA cell cultures. Overall, our results suggest that GHRH antagonists, either alone or in combination with pharmacological treatments, may be considered for further development as therapy for PAs. |
| first_indexed | 2024-03-10T08:57:29Z |
| format | Article |
| id | doaj.art-63523964bbe34b3f9ab1d3fd5db9a49b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T08:57:29Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-63523964bbe34b3f9ab1d3fd5db9a49b2023-11-22T07:01:36ZengMDPI AGCancers2072-66942021-08-011316395010.3390/cancers13163950Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic SignalingIacopo Gesmundo0Giuseppina Granato1Antonio C. Fuentes-Fayos2Clara V. Alvarez3Carlos Dieguez4Maria Chiara Zatelli5Noemi Congiusta6Dana Banfi7Nunzia Prencipe8Sheila Leone9Luigi Brunetti10Justo P. Castaño11Raúl M. Luque12Renzhi Cai13Wei Sha14Ezio Ghigo15Andrew V. Schally16Riccarda Granata17Division of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, 10126 Turin, ItalyDivision of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, 10126 Turin, ItalyMaimonides Institute for Biomedical Research of Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Córdoba and Reina Sofia University Hospital, 14004 Córdoba, SpainCentro de Investigaciones Médicas (CIMUS) e Instituto de Investigaciones Sanitarias, University of Santiago de Compostela and Complexo Hospitalario Universitario of Santiago de Compostela, 14004 Santiago de Compostela, SpainCentro de Investigaciones Médicas (CIMUS) e Instituto de Investigaciones Sanitarias, University of Santiago de Compostela and Complexo Hospitalario Universitario of Santiago de Compostela, 14004 Santiago de Compostela, SpainSection of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, 15706 Ferrara, ItalyDivision of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, 10126 Turin, ItalyDivision of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, 10126 Turin, ItalyDivision of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, 10126 Turin, ItalyDepartment of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyMaimonides Institute for Biomedical Research of Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Córdoba and Reina Sofia University Hospital, 14004 Córdoba, SpainMaimonides Institute for Biomedical Research of Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Córdoba and Reina Sofia University Hospital, 14004 Córdoba, SpainDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USADivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USADivision of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, 10126 Turin, ItalyDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USADivision of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, 10126 Turin, ItalyPituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticancer effects, and early GHRH antagonists were found to inhibit GHRH-induced secretion of pituitary GH in vitro and in vivo. However, the antitumor role of GHRH antagonists in PAs is largely unknown. Here, we show that the GHRH antagonists of MIAMI class, MIA-602 and MIA-690, inhibited cell viability and growth and promoted apoptosis in GH/prolactin-secreting GH3 PA cells transfected with human GHRH receptor (GH3-GHRHR), and in adrenocorticotropic hormone ACTH-secreting AtT20 PA cells. GHRH antagonists also reduced the expression of proteins involved in tumorigenesis and cancer progression, upregulated proapoptotic molecules, and lowered GHRH receptor levels. The combination of MIA-690 with temozolomide synergistically blunted the viability of GH3-GHRHR and AtT20 cells. Moreover, MIA-690 reduced both basal and GHRH-induced secretion of GH and intracellular cAMP levels. Finally, GHRH antagonists inhibited cell viability in human primary GH- and ACTH-PA cell cultures. Overall, our results suggest that GHRH antagonists, either alone or in combination with pharmacological treatments, may be considered for further development as therapy for PAs.https://www.mdpi.com/2072-6694/13/16/3950GHRHGH-secreting pituitary adenomaACTH-secreting pituitary adenomascell viabilityapoptosis |
| spellingShingle | Iacopo Gesmundo Giuseppina Granato Antonio C. Fuentes-Fayos Clara V. Alvarez Carlos Dieguez Maria Chiara Zatelli Noemi Congiusta Dana Banfi Nunzia Prencipe Sheila Leone Luigi Brunetti Justo P. Castaño Raúl M. Luque Renzhi Cai Wei Sha Ezio Ghigo Andrew V. Schally Riccarda Granata Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling Cancers GHRH GH-secreting pituitary adenoma ACTH-secreting pituitary adenomas cell viability apoptosis |
| title | Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling |
| title_full | Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling |
| title_fullStr | Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling |
| title_full_unstemmed | Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling |
| title_short | Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling |
| title_sort | antagonists of growth hormone releasing hormone inhibit the growth of pituitary adenoma cells by hampering oncogenic pathways and promoting apoptotic signaling |
| topic | GHRH GH-secreting pituitary adenoma ACTH-secreting pituitary adenomas cell viability apoptosis |
| url | https://www.mdpi.com/2072-6694/13/16/3950 |
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