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

Kinga Németh, Nikolette Szücs, S. Czirják, Lilla Reiniger, Borbála Szabó, G. Barna, Katalin Karászi, P. Igaz, Vladimir Zivkovic, Márta Korbonits, A. Patócs, Henriett Butz

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)29180-29192
Number of pages13
JournalOncotarget
Volume9
Issue number49
DOIs
Publication statusPublished - Jun 26 2018

Fingerprint

Pituitary Neoplasms
Aspirin
TNF-Related Apoptosis-Inducing Ligand
Cyclin-Dependent Kinase 2
Therapeutics
Cell Cycle
Heterografts
Small Interfering RNA
Cyclin A
G2 Phase
Growth
S Phase
Caspase 3
Cell Division
Adenoma
Antineoplastic Agents
Growth Hormone
Cell Survival
Flow Cytometry
Down-Regulation

Keywords

  • Acetylsalicylic acid
  • Cell cycle
  • Nonfunctioning adenoma
  • Pituitary adenoma
  • Survivin

ASJC Scopus subject areas

  • Oncology

Cite this

Survivin as a potential therapeutic target of acetylsalicylic acid in pituitary adenomas. / Németh, Kinga; Szücs, Nikolette; Czirják, S.; Reiniger, Lilla; Szabó, Borbála; Barna, G.; Karászi, Katalin; Igaz, P.; Zivkovic, Vladimir; Korbonits, Márta; Patócs, A.; Butz, Henriett.

In: Oncotarget, Vol. 9, No. 49, 26.06.2018, p. 29180-29192.

Research output: Contribution to journalArticle

Németh, K, Szücs, N, Czirják, S, Reiniger, L, Szabó, B, Barna, G, Karászi, K, Igaz, P, Zivkovic, V, Korbonits, M, Patócs, A & Butz, H 2018, 'Survivin as a potential therapeutic target of acetylsalicylic acid in pituitary adenomas', Oncotarget, vol. 9, no. 49, pp. 29180-29192. https://doi.org/10.18632/oncotarget.25650
Németh, Kinga ; Szücs, Nikolette ; Czirják, S. ; Reiniger, Lilla ; Szabó, Borbála ; Barna, G. ; Karászi, Katalin ; Igaz, P. ; Zivkovic, Vladimir ; Korbonits, Márta ; Patócs, A. ; Butz, Henriett. / Survivin as a potential therapeutic target of acetylsalicylic acid in pituitary adenomas. In: Oncotarget. 2018 ; Vol. 9, No. 49. pp. 29180-29192.
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