Wang Meng, Liu Chang, Li Yuehan, Zhang Qiulin, Zhu Lixia, Fang Zishui, Jin Lei
Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Reproductive Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Oncol. 2020 Sep 3;10:1781. doi: 10.3389/fonc.2020.01781. eCollection 2020.
Accumulated evidence has shown that the photosensitizer Verteporfin (VP) may be an ideal agent for various cancer types. However, the effect and mechanism of VP on human cervical carcinoma remain rudimentary. The aim of this study was to investigate the effect of VP on human cervical carcinoma cells (HeLa and SiHa cells) and to elucidate the possible mechanism. CCK-8, wound healing assay, flow cytometry analysis, western blotting, TUNEL staining were performed to evaluate the effects of VP on HeLa and SiHa cells as well as on a xenograft model. In addition, the role of endoplasmic reticulum (ER) stress in VP-induced apoptosis was investigated using RT-qPCR and western blotting. The results showed that the viability of HeLa and SiHa cells was suppressed by VP in dose- and time-dependent manners. Compared with the control group, apoptosis rates were higher with stronger TUNEL fluorescence signals in the experimental group, which substantiated that VP induced apoptosis at both 2D and 3D cell levels. Besides, VP can squelch the growth of tumors in both sizes and weights on the xenograft models without impairing ovarian reserve. Mechanism studies demonstrated that VP activated ER stress by upregulating the expression of GRP78, CHOP, and Caspase-12, and VP-induced apoptosis can be alleviated when ER stress pathway was inhibited. Our results provided a foundation for repurposing VP as a promising agent for cervical cancer patients without obvious reproductive toxicity by targeting ER stress pathway, and more researches are required to support its application in clinical practice.
越来越多的证据表明，光敏剂维替泊芬（VP）可能是治疗多种癌症类型的理想药物。然而，VP对人宫颈癌的作用及机制仍不清楚。本研究旨在探讨VP对人宫颈癌细胞（HeLa和SiHa细胞）的影响，并阐明其可能的机制。采用CCK-8、伤口愈合试验、流式细胞术分析、蛋白质印迹法、TUNEL染色等方法，评估VP对HeLa和SiHa细胞以及异种移植模型的影响。此外，利用RT-qPCR和蛋白质印迹法研究内质网（ER）应激在VP诱导的细胞凋亡中的作用。结果表明，VP以剂量和时间依赖性方式抑制HeLa和SiHa细胞的活力。与对照组相比，实验组的凋亡率更高，TUNEL荧光信号更强，这证实了VP在二维和三维细胞水平上均能诱导细胞凋亡。此外，VP可抑制异种移植模型中肿瘤的大小和重量增长，且不损害卵巢储备功能。机制研究表明，VP通过上调GRP78、CHOP和Caspase-12的表达激活ER应激，当ER应激途径被抑制时，VP诱导的细胞凋亡可得到缓解。我们的研究结果为将VP重新用作治疗宫颈癌患者的有前景药物奠定了基础，该药物通过靶向ER应激途径且无明显生殖毒性，并且需要更多研究来支持其在临床实践中的应用。
