神经酰胺激酶通过调节神经酰胺和C1P水平有效抑制顺铂耐药卵巢癌细胞

IF 2 4区 医学 Q2 OBSTETRICS & GYNECOLOGY
Jing Zou, Long Jian
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引用次数: 0

摘要

目的:卵巢癌的化疗耐药导致治疗失败,但调节化疗耐药的潜在机制仍不清楚。越来越多的证据表明卵巢癌耐药与生物活性鞘脂和鞘脂代谢调节有关。研究了神经酰胺激酶(CerK)在卵巢癌中的表达和功能,以及靶向CerK的治疗潜力。CerK是一种调节中枢生物活性鞘脂的脂质激酶。设计:测定卵巢癌和正常卵巢癌中神经酰胺、神经酰胺1-磷酸(C1P)和Cerk的水平。探讨了Cerk在卵巢癌中的作用。材料、环境、方法:采用免疫组织化学、ELISA和质谱法测定原代组织中神经酰胺、C1P和CerK的水平。在没有或存在顺铂的情况下,对CERK缺失、CERK过表达和NVP-231治疗后的卵巢癌细胞进行增殖和凋亡检测。结果:与正常卵巢细胞相比,卵巢癌组织中CerK及其介导的生物活性鞘脂、神经酰胺和C1P均降低。有趣的是,顺铂耐药卵巢癌细胞表现为CerK升高,神经酰胺降低,C1P升高,并且卵巢癌细胞中CerK水平与神经酰胺和C1P水平密切相关。功能分析表明,CerK过表达足以促进卵巢癌细胞的生长并赋予化疗耐药。通过遗传和药理学方法抑制CerK抑制顺铂耐药细胞的生长和诱导凋亡,而且这显著增强了顺铂的疗效。局限性:对体外卵巢癌细胞进行了C1P的功能分析。体内研究需要进一步证实CERK抑制的作用。结论:我们的研究首次揭示了CerK通过调节神经酰胺和C1P在卵巢癌化疗耐药机制中的关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of Ceramide Kinase Is Effective against Cisplatin-Resistant Ovarian Cancer Cells by Regulating Ceramide and C1P Levels.

Objective: Chemoresistance in ovarian cancer results in treatment failure, yet underlying mechanisms that regulate chemoresistance remain largely unclear. There is emerging evidence relating ovarian cancer drug resistance with bioactive sphingolipids and regulation of sphingolipid metabolism. This work investigated the expression and function of ceramide kinase (CerK), a lipid kinase that regulates central bioactive sphingolipids, in ovarian cancer, as well as the therapeutic potential of targeting CERK.

Design: The levels of ceramide, ceramide 1-phosphate (C1P), and Cerk in ovarian cancer and normal counterparts were measured. Functions of Cerk in ovarian cancer were examined.

Materials, setting, methods: Immunohistochemistry, ELISA, and mass spectrometry methods were used to measure the level of ceramides, C1P, and CerK in primary tissues. Proliferation and apoptosis assays were performed in ovarian cancer cells after CERK depletion, CERK overexpression, and NVP-231 treatment in the absence or presence of cisplatin.

Results: Compared to normal ovarian cells, CerK and its mediating bioactive sphingolipids ceramide and C1P were decreased in ovarian cancer tissues. Interestingly, cisplatin-resistant ovarian cancer cells displayed increased CerK, decreased ceramide, and increased C1P, and furthermore, that CerK level was closely associated with ceramide and C1P levels in ovarian cancer cells. Functional analysis demonstrated that CerK overexpression was sufficient to promote growth and confer chemoresistance in ovarian cancer cells. CerK inhibition via both genetic and pharmacological approaches suppressed growth and induced apoptosis in cisplatin-resistant cells, and furthermore, this significantly augmented cisplatin's efficacy.

Limitations: The functional analysis of C1P was performed on in vitro ovarian cancer cells. In vivo studies were needed to further confirm the effects of CERK inhibition.

Conclusions: Our work is the first to show the critical role of CerK as the underlying mechanism of ovarian cancer chemoresistance, through regulating ceramide and C1P.

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来源期刊
CiteScore
4.20
自引率
4.80%
发文量
44
审稿时长
6-12 weeks
期刊介绍: This journal covers the most active and promising areas of current research in gynecology and obstetrics. Invited, well-referenced reviews by noted experts keep readers in touch with the general framework and direction of international study. Original papers report selected experimental and clinical investigations in all fields related to gynecology, obstetrics and reproduction. Short communications are published to allow immediate discussion of new data. The international and interdisciplinary character of this periodical provides an avenue to less accessible sources and to worldwide research for investigators and practitioners.
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