Cancer & Exosome Biology Laboratory, Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysuru, 570020, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Mol Biol Rep. 2024 Sep 2;51(1):949. doi: 10.1007/s11033-024-09875-x.
Cervical cancer ranks as the fourth most prevalent cancer among women globally, presenting a significant therapeutic challenge due to its resistance to cisplatin. Ephrin type-A receptor 2 (EPHA2) is prominently overexpressed in cervical cancer and plays a vital role in cisplatin resistance, although the underlying mechanisms remain incompletely elucidated. Mitochondrial dynamics, autophagy, and mitophagy are critical in mediating cisplatin resistance. Sesamol, a phytochemical compound, has exhibited promising anticancer properties. This study aims to investigate the regulatory role of EPHA2 in these pathways underlying cisplatin resistance and to investigate the potential of sesamol in overcoming this resistance and inhibiting cervical cancer progression.
In this study, we knocked down EPHA2 in the SiHa cell line and evaluated the resulting changes in molecular markers associated with mitochondrial dynamics, mitophagy, and autophagy. Our results indicated that EPHA2 knockdown (EPHA2-KD) led to enhanced mitochondrial fusion and reduced mitochondrial fission, mitophagy, and autophagy. Furthermore, we investigated the effect of EPHA2-KD and sesamol treatment on sensitising cervical cancer to cisplatin treatment. Our data revealed that EPHA2-KD and sesamol treatment significantly increases cellular sensitivity to cisplatin-induced cytotoxicity. Additionally, we demonstrated that sesamol effectively targets EPHA2, as evidenced by decreased EPHA2 expression levels following sesamol treatment.
In summary, targeting EPHA2 through knockdown or sesamol treatment enhances cisplatin sensitivity in cervical cancer by modulating mitochondrial dynamics, autophagy and mitophagy, suggesting promising therapeutic strategies to overcome chemoresistance.
宫颈癌是全球女性第四大常见癌症，由于其对顺铂的耐药性，治疗极具挑战性。Ephrin 型-A 受体 2（EPHA2）在宫颈癌中过表达，在顺铂耐药中发挥重要作用，但其潜在机制尚不完全清楚。线粒体动力学、自噬和噬线粒体在介导顺铂耐药中起着关键作用。芝麻酚，一种植物化学物质，表现出有希望的抗癌特性。本研究旨在探讨 EPHA2 在这些介导顺铂耐药的途径中的调节作用，并研究芝麻酚克服这种耐药性和抑制宫颈癌进展的潜力。
在这项研究中，我们敲低了 SiHa 细胞系中的 EPHA2，并评估了与线粒体动力学、噬线粒体和自噬相关的分子标记物的变化。结果表明，EPHA2 敲低（EPHA2-KD）导致线粒体融合增强，线粒体裂变、噬线粒体和自噬减少。此外，我们研究了 EPHA2-KD 和芝麻酚处理对增强宫颈癌对顺铂治疗敏感性的影响。我们的数据表明，EPHA2-KD 和芝麻酚处理显著增加了细胞对顺铂诱导的细胞毒性的敏感性。此外，我们证明芝麻酚可有效靶向 EPHA2，因为芝麻酚处理后 EPHA2 表达水平降低。
总之，通过敲低或芝麻酚处理靶向 EPHA2 可通过调节线粒体动力学、自噬和噬线粒体来增强宫颈癌对顺铂的敏感性，提示有希望的治疗策略来克服化疗耐药性。
