Cisplatin Induces Resistance by Triggering Differentiation of Testicular Embryonal Carcinoma Cells
Cisplatin Induces Resistance by Triggering Differentiation of Testicular Embryonal Carcinoma Cells
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DOI：
10.1371/journal.pone.0087444
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发表时间：
2014-01-27
期刊：
影响因子：
3.7
通讯作者：
Howell, Stephen B.
中科院分区：
文献类型：
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作者：
Abada, Paolo B.;Howell, Stephen B.
尽管睾丸生殖细胞肿瘤通常对顺铂治疗非常敏感，但其中一小部分在治疗过程中产生了耐药性。即使顺铂治疗成功，患者也常常在原发肿瘤部位留下残余畸胎瘤，这表明顺铂可能引发某些肿瘤的分化。使用人胚胎癌细胞系 NTera2/D1，我们证实暴露于分化剂视黄酸会导致多能性标记物 NANOG 和 POU5F1 (Oct3/4) 减少，并且对顺铂和紫杉醇的耐药性急剧浓度依赖性增加，四天内顺铂高达 18 倍，紫杉醇高达 61 倍。暴露于顺铂两天后，NANOG 和 POU5F1 的表达也出现浓度依赖性下降，并且三种标记物的表达增加，这三种标记物的水平随着分化而增加，包括巢蛋白、SCG10 和纤连蛋白。与此同时，暴露于顺铂诱导了高达 6.2 倍的耐药性和 104 倍的紫杉醇耐药性。紫杉醇不诱导分化或对其本身或顺铂的抗性。视黄酸和顺铂均未诱导宫颈癌细胞系或前列腺癌细胞系或其他生殖细胞肿瘤系产生耐药性，在这些细胞系中，它们未能改变 NANOG 和 POU5F1 的表达。 NANOG 的强制表达阻止了视黄酸诱导的顺铂耐药性。我们得出的结论是，顺铂可以通过触发多能生殖细胞肿瘤细胞的分化反应，急性诱导对其自身和紫杉醇的耐药性。
Although testicular germ cell tumors are generally quite responsive to treatment with cisplatin, a small fraction of them acquire resistance during therapy. Even when cisplatin treatment is successful the patient is often left with a residual teratoma at the site of the primary tumor suggesting that cisplatin may trigger differentiation in some tumors. Using the human embryonal carcinoma cell line NTera2/D1, we confirmed that exposure to the differentiating agent retinoic acid produced a reduction in pluripotency markers NANOG and POU5F1 (Oct3/4) and an acute concentration-dependent increase in resistance to both cisplatin and paclitaxel that reached as high as 18-fold for cisplatin and 61-fold for paclitaxel within four days. A two day exposure to cisplatin also produced a concentration-dependent decrease in the expression of the NANOG and POU5F1 and increased expression of three markers whose levels increase with differentiation including Nestin, SCG10 and Fibronectin. In parallel, exposure to cisplatin induced up to 6.2-fold resistance to itself and 104-fold resistance to paclitaxel. Paclitaxel did not induce differentiation or resistance to either itself or cisplatin. Neither retinoic acid nor cisplatin induced resistance in cervical or prostate cancer cell lines or other germ cell tumor lines in which they failed to alter the expression of NANOG and POU5F1. Forced expression of NANOG prevented the induction of resistance to cisplatin by retinoic acid. We conclude that cisplatin can acutely induce resistance to itself and paclitaxel by triggering a differentiation response in pluripotent germ cell tumor cells.