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.
Mol Med Rep. 2023 Apr;27(4). doi: 10.3892/mmr.2023.12968. Epub 2023 Feb 24.
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.
信号转导子和转录激活子 3（STAT3）信号在致癌作用和细胞衰老中起重要作用，其在肿瘤细胞中的抑制作用代表了一个有吸引力的治疗靶点。细胞衰老，即细胞对各种诱导剂（如细胞毒性药物或电离辐射）的永久增殖停滞，伴随着形态和分泌的变化，以及对化疗药物敏感性的改变，这可能会使癌症治疗更难消除肿瘤。在本研究中，使用肿瘤细胞系评估了增殖细胞和多西紫杉醇（DTX）诱导的衰老癌细胞对小分子 STAT3 抑制剂 Stattic 及其类似物的反应性。这些药物在增殖和衰老的小鼠 TRAMP-C2 和 TC-1 细胞的细胞活力测定中均表现出细胞毒性作用；然而，衰老细胞的耐药性明显更强。Western blot 分析显示，Stattic 和其类似物可有效抑制增殖和衰老细胞中组成型 STAT3 磷酸化。此外，还评估了 Stattic 衍生的抑制剂 K1836 是否会影响衰老的诱导或调节衰老细胞的表型。K1836 处理对 DTX 诱导的衰老无影响。然而，K1836 化合物可显著调节某些细胞因子（白细胞介素 6、生长调节致癌基因 α 和单核细胞趋化蛋白-1）的分泌。综上所述，本研究表明增殖和衰老肿瘤细胞在对 STAT3 抑制剂的敏感性方面存在差异，并证明了新型 STAT3 抑制剂 K1836 能够影响衰老相关分泌表型的重要组成部分的分泌。本研究可能有助于进一步开发基于 STAT3 抑制剂的癌症或与年龄相关疾病的治疗方法。
