Research Papers:

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

Kinga Németh, Nikolette Szücs, Sándor Czirják, Lilla Reiniger, Borbála Szabó, Gábor Barna, Katalin Karászi, Péter Igaz, Vladimir Zivkovic, Márta Korbonits, Attila Patócs and Henriett Butz _

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Oncotarget. 2018; 9:29180-29192. https://doi.org/10.18632/oncotarget.25650

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Kinga Németh1, Nikolette Szücs1, Sándor Czirják2, Lilla Reiniger3, Borbála Szabó4, Gábor Barna3, Katalin Karászi3, Péter Igaz1,5, Vladimir Zivkovic6, Márta Korbonits7, Attila Patócs4,8 and Henriett Butz4,8

12nd Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary

2National Institute of Clinical Neurosciences, Budapest, Hungary

31st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

4Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary

5MTA-SE Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

6University Clinical Centre, Belgrade, Serbia

7Department of Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom

8MTA-SE “Lendulet” Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

Correspondence to:

Henriett Butz, email: [email protected]

Keywords: pituitary adenoma; nonfunctioning adenoma; cell cycle; survivin; acetylsalicylic acid

Received: April 04, 2018     Accepted: June 04, 2018     Published: June 26, 2018


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.

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