Survivin as a potential therapeutic target of acetylsalicylic acid in pituitary adenomas

Abstract

Acetylsalicylic acid (ASA) is known as a cancer preventing agent, but there is no data available regarding the effect of ASA on pituitary cells.We investigated 66 nonfunctioning (NFPA) and growth hormone (GH)-producing adenomas and 15 normal pituitary samples. Functional assays (cell viability, proliferation, flow cytometry cell cycle analysis, caspase-3 activation and DNA degradation) were applied to explore the effect of ASA, YM155 (survivin inhibitor), survivin-targeting siRNA and TNF-related apoptosis-inducing ligand (TRAIL) in RC-4B/C and GH3 cells. Pituitary adenoma xenografts were generated in immunocompromised mice.We found that survivin was overexpressed and TRAIL was downregulated in NFPAs compared to normal pituitary tissue. ASA decreased proliferation but did not induce apoptosis in pituitary cells. Additionally, ASA treatment decreased cells in S phase and increased cells in G2/M phase of the cell cycle. Inhibition of survivin using an inhibitor or siRNA-mediated silencing reversed the ASA-induced growth inhibition partially. In addition, we also found survivin-independent effects of ASA on the cell cycle that were mediated through inhibition of cyclin A, cyclin dependent kinase 2 (CDK2) and phospho-CDK2. We also aimed to test the effect of acetylsalicylic acid in an animal model using RC-4 B/C cells, but in contrast to GH3 cells, RC-4 B/C cells failed to adhere and grow a xenograft.We concluded that ASA inhibited the growth of pituitary adenoma cells. Survivin inhibition is a key mechanism explaining its antineoplastic effects. Our results suggest that inhibition of survivin with small molecules or ASA could serve as potential therapeutic agents in NFPA.

RC-4BC cells express nicotinic and muscarinic acetylcholine receptors

“…potential of drugs for treatment of pituitary adenomas [22]. In the current study we aimed to investigate the expression of different subunits of acetylcholine receptors.…”

The use of mass spectrometry in a proteome‐centered multiomics study of human pituitary adenomas

“…Peptides presented in human body fluids, cells, and tissues, and bioactive peptides, play crucial roles in multiple physiological functions such as hormonal messengers, antimicrobial agents, immune performance, cytokines, signal transduction, antiviral agent, cell‐cell communication, and protease inhibitors (Schrader, 2018). Peptidomics has several important applications, including candidate bioactive peptides, disease biomarkers, neuropeptidomics, and mapping dietary protein digestion (Dallas et al, 2015).…”

“…Based on this evidence, thiazolidinediones might be one way to clinically manage Cushing's disease (Heaney et al, 2002). Acetylsalicylic acid or survivin small‐molecule inhibitors decreased proliferation and regulated cell cycles (S and G2/M phase) to inhibit PA cell growth (Németh et al, 2018). The downregulated expression of lncRNA H19 was significantly associated with PA tumorigenesis and progression (Wu et al, 2018).…”

Untitled

“…In the publication by Németh K et al, [8], they described the role of survivin in pituitary adenomas (PAs) as well as a new mechanism by which the apoptotic effect of ASA can be used to target PA cells. Representing approximately 20% of intracranial neoplasms, PAs are considered the third most frequent intracranial neoplastic tumor type, shadowing only meningiomas and glioblastomas [9].…”

“…The current study [8] is a useful and well-written addition to the literature involving antitumor effects of ASA via the survivin pathway. They demonstrated that from the various pituitary tissue types they analyzed, survivin was overexpressed only in the NFPAs.…”