Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Circuito Escolar S/N, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, México.
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Circuito Escolar S/N, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, México.
Oncol Rep. 2019 Feb;41(2):1333-1341. doi: 10.3892/or.2018.6890. Epub 2018 Nov 27.
Erythropoietin (Epo) is used for the treatment of cancer‑associated anaemia. However, certain studies have identified that the administration of Epo mediates the acquisition of resistance to cisplatin, which is widely used to treat cervical cancer. Our group previously reported that cervical cancer cells express Epo receptor and that exogenous Epo induces cell proliferation and migration. However, the effect of Epo on cervical cancer cell death mediated by chemotherapeutic agents has not yet been evaluated. Thus, the aim of the present study was to assess the potential effect of Epo on the cytotoxic activity of cisplatin in cervical cancer cells. The effect of Epo was assessed in 3 cervical cancer‑derived cell lines. It was observed that pre‑incubation with Epo induced a significant reduction of cisplatin‑induced apoptosis in vitro and in vivo. Incubation with Epo induced the expression and activation of the transcriptional factor signal transducer and activator of transcription 3 (STAT3), which in turn stimulated the expression and activation of the anti‑apoptotic protein survivin. The cytotoxicity of cisplatin was partially restored by treating the cells with MY155, an inhibitor of survivin. Conversely, inhibition of STAT3 activation using sub‑lethal doses of WP1066, completely abolished the cytoprotective effect of Epo. These observations indicated that Epo was able to hinder the cytotoxic effect of cisplatin in cervical cancer cells by activating anti‑apoptotic responses regulated by STAT3.
促红细胞生成素 (Epo) 被用于治疗癌症相关性贫血。然而，某些研究表明，Epo 的给药会介导对顺铂的耐药性获得，顺铂被广泛用于治疗宫颈癌。我们的研究小组先前报道了宫颈癌细胞表达 Epo 受体，外源性 Epo 可诱导细胞增殖和迁移。然而，Epo 对化疗药物介导的宫颈癌细胞死亡的影响尚未得到评估。因此，本研究旨在评估 Epo 对宫颈癌细胞中顺铂细胞毒性的潜在影响。在 3 种宫颈癌衍生细胞系中评估了 Epo 的作用。结果观察到，Epo 的预孵育可显著减少体外和体内顺铂诱导的细胞凋亡。Epo 的孵育诱导转录因子信号转导和转录激活因子 3 (STAT3) 的表达和激活，进而刺激抗凋亡蛋白 survivin 的表达和激活。用 MY155（survivin 的抑制剂）处理细胞可部分恢复顺铂的细胞毒性。相反，使用亚致死剂量的 WP1066 抑制 STAT3 激活可完全消除 Epo 的细胞保护作用。这些观察结果表明，Epo 通过激活由 STAT3 调节的抗凋亡反应，能够阻碍宫颈癌细胞中顺铂的细胞毒性作用。
