STAT3 inhibitor Stattic and its analogues inhibit STAT3 phosphorylation and modulate cytokine secretion in senescent tumour cells.
Mol Med Rep
; 27(4)2023 04.
Article
in En
| MEDLINE
| ID: mdl-36825563
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 TRAMPC2 and TC1 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 Statticderived 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 (interleukin6, growthregulated oncogene α and monocyte chemoattractant protein1). 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 senescenceassociated secretory phenotype. The present study may be useful for further development of STAT3 inhibitorbased therapy of cancer or agerelated diseases.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cytokines
/
STAT3 Transcription Factor
Limits:
Animals
Language:
En
Journal:
Mol Med Rep
Year:
2023
Document type:
Article
Affiliation country:
Czech Republic