STAT3 inhibitor Stattic and its analogues inhibit STAT3 phosphorylation and modulate cytokine secretion in senescent tumour cells

Mikyskova,Romana; Sapega,Olena; Psotka,Miroslav; Novotny,Ondrej; Hodny,Zdeněk; Balintova,Sona; Malinak,David; Svobodova,Jana; Andrys,Rudolf; Rysanek,David; Musilek,Kamil; Reinis,Milan

doi:10.3892/mmr.2023.12968

STAT3 inhibitor Stattic and its analogues inhibit STAT3 phosphorylation and modulate cytokine secretion in senescent tumour cells

Authors:
- Romana Mikyskova
- Olena Sapega
- Miroslav Psotka
- Ondrej Novotny
- Zdeněk Hodny
- Sona Balintova
- David Malinak
- Jana Svobodova
- Rudolf Andrys
- David Rysanek
- Kamil Musilek
- Milan Reinis
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Affiliations: Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of The Czech Academy of Sciences, 142 20 Prague, Czech Republic, Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of The Czech Academy of Sciences, 142 20 Prague, Czech Republic, Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03 Hradec Kralove, Czech Republic, Laboratory of Genome Integrity, Institute of Molecular Genetics of The Czech Academy of Sciences, 142 20 Prague, Czech Republic
Published online on: February 22, 2023 https://doi.org/10.3892/mmr.2023.12968
Article Number: 81
Copyright : © Mikyskova et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

Signal transducer and activator of transcription 3 (STAT3) signalling serves an important role in carcinogenesis and cellular senescence, and its inhibition in tumour cells represents an attractive therapeutic target. Premature cellular senescence, a process of permanent proliferative arrest of cells in response to various inducers, such as cytostatic drugs or ionizing radiation, is accompanied by morphological and secretory changes, and by altered susceptibility to chemotherapeutic agents, which can thereby complicate their eradication by cancer therapies. In the present study, the responsiveness of proliferating and docetaxel (DTX)‑induced senescent cancer cells to small molecule STAT3 inhibitor Stattic and its analogues was evaluated using tumour cell lines. These agents displayed cytotoxic effects in cell viability assays on both proliferating and senescent murine TRAMP‑C2 and TC‑1 cells; however, senescent cells were markedly more resistant. Western blot analysis revealed that Stattic and its analogues effectively inhibited constitutive STAT3 phosphorylation in both proliferating and senescent cells. Furthermore, whether the Stattic‑derived inhibitor K1836 could affect senescence induction or modulate the phenotype of senescent cells was evaluated. K1836 treatment demonstrated no effect on senescence induction by DTX. However, the K1836 compound significantly modulated secretion of certain cytokines (interleukin‑6, growth‑regulated oncogene α and monocyte chemoattractant protein‑1). In summary, the present study demonstrated differences between proliferating and senescent tumour cells in terms of their susceptibility to STAT3 inhibitors and demonstrated the ability of the new STAT3 inhibitor K1836 to affect the secretion of essential components of the senescence‑associated secretory phenotype. The present study may be useful for further development of STAT3 inhibitor‑based therapy of cancer or age‑related diseases.

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