Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling.

Iacopo Gesmundo,Riccarda Granata,Clara V Alvarez,Nunzia Prencipe,Ezio Ghigo,Renzhi Cai,Sheila Leone,Noemi Congiusta,Justo P Castaño,Antonio C Fuentes-Fayos,Luigi Brunetti,Giuseppina Granato,Maria Chiara Zatelli,Dana Banfi,Andrew V Schally,Carlos Dieguez,Wei Sha,Raúl M Luque

doi:10.3390/cancers13163950

Abstract

Simple SummaryMany studies have demonstrated that the antagonists of growth hormone-releasing hormone (GHRH) exert inhibitory activities in a variety of experimental cancers; however, their potential antitumor role in pituitary adenomas (PAs) remains largely unknown. Here, we show that GHRH antagonists of Miami (MIA) class, MIA-602 and MIA-690, are able to reduce the growth and promote cell death in hormone-secreting PA cell lines, through the inhibition of mechanisms implicated in tumorigenesis and cancer progression. MIA-602 and MIA-690 also decreased the viability of tumor cells derived from human pituitary tumors. Overall, these findings suggest that GHRH antagonists may represent new therapeutic tools for the treatment of PAs, both alone or in combination with standard pharmacological treatments.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.

Highlights

Pituitary adenomas (PAs) originating from the anterior pituitary are usually benign lesions, yet they often cause comorbidities and syndromes related to local mass effects or hormonal excess
As GH3 cells do not constitutively express growth hormone-releasing hormone (GHRH)-R [38], the presence of mRNA for GHRH-R was first verified in somatolactotroph GH3 cells stably transfected with human cDNA for GHRH-R, namely GH3-GHRHR cells [33]
Real-time PCR experiments showed that, while GH3 cells were negative for both rat and human GHRH-R mRNAs, human, but not rat, GHRH-R mRNA, was present in GH3-GHRHR cells (Figure 1A)

Summary

Introduction

Pituitary adenomas (PAs) originating from the anterior pituitary are usually benign lesions, yet they often cause comorbidities and syndromes related to local mass effects or hormonal excess. PAs are heterogenous and complex, showing a multitude of proliferative and hormonal behaviors They can either grow rapidly and promote symptoms related to intracranial mass, such as headaches, visual disorders, or hypopituitarism, or produce hormones in excess, causing severe syndromes, such as Cushing’s disease or acromegaly, increasing morbidity and mortality [4]. The alkylating agent, temozolomide (TMZ), is used for aggressive PRL-PAs, NFPAs, GH-Pas, or ACTH-PAs and carcinomas [6,7] These drugs are usually effective in reducing hormone hypersecretion and promoting tumor shrinkage, some patients are drug-resistant and several adverse effects have been reported. Development of new drugs to treat PAs has become an urgent issue

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