Additive effects of C2-ceramide on paclitaxel-induced premature senescence of human lung cancer cells
Additive effects of C2-ceramide on paclitaxel-induced premature senescence of human lung cancer cells
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DOI：
10.1016/j.lfs.2010.06.017
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发表时间：
2010-09-11
期刊：
影响因子：
6.1
通讯作者：
Chiu, Chien-Chih
中科院分区：
文献类型：
--
作者：
Chen, Jeff Yi-Fu;Hwang, Chi-Ching;Chiu, Chien-Chih
目的：研究外源性短碳链磷脂c -2-神经酰胺对抗癌药物紫杉醇（PTX）诱导的缺乏功能性p53和p16的人非小细胞肺癌（NSCLC）细胞衰老的加性作用，并探讨丝裂原活化蛋白激酶（MAPK）是否在神经酰胺致敏的NSCLC细胞衰老中发挥作用。主要方法：为了确定外源性c -2神经酰胺是否使肺癌细胞对PTX治疗更敏感，使用了基于流式细胞术的细胞周期分析和衰老细胞酸性β -半乳糖苷酶染色技术。此外，为了阐明MAPK蛋白在调节衰老中的作用，研究中使用了选择性MAPK和Bcl-2家族成员的蛋白水平检测，以及衰老相关基因的转录水平检测。主要发现：亚致死剂量的c -2神经酰胺使NSCLC H1299细胞对PTX治疗增敏。c -2-神经酰胺和PTX的叠加作用导致细胞增殖抑制，细胞周期G(2)期阻滞，p38活化，最终导致过早衰老。重要的是，在我们的研究中，p53、p21（waf1/cip1）和p16（ink4）均未被发现参与PTX致敏的c -2神经酰胺对H1299细胞的增殖抑制和衰老。意义：我们的研究表明，短碳链c2 -神经酰胺可以通过p21(waf1/cip1)-和p16(ink4)-独立途径有效地敏化ptx诱导的H1299细胞衰老。(C) 2010爱思唯尔公司版权所有。
Aims: The aims of the study are to investigate the additive effect of exogenous short-carbon chain phospholipids, C-2-ceramide, on an anti-cancer drug paclitaxel (PTX)-induced senescence of human non-small cell lung cancer (NSCLC) cells deficient in functional p53 and p16, and to examine whether mitogen-activated protein kinase (MAPK) plays a role in ceramide-sensitized senescence of NSCLC cells.Main methods: To determine whether exogenous C-2-ceramide renders lung cancer cells more sensitive to PTX treatment, techniques employing a flow cytometry-based cell cycle analysis and acidic beta-galactosidase staining for senescent cells were used. Furthermore, to elucidate the role of MAPK proteins in modulating senescence, assays for protein levels of selective MAPKs and Bcl-2 family members, and detection of transcriptional levels senescence-associated genes were used in the study.Key findings: A sub-lethal dose of C-2-ceramide sensitized the NSCLC H1299 cells to PTX treatment. The additive effects of C-2-ceramide and PTX resulted in proliferative inhibition, G(2)-phase arrest of cell cycle, activation of p38 and eventually premature senescence. Importantly, neither p53, p21(waf1/cip1) nor p16(ink4) was shown to be involved in C-2-ceramide-sensitized proliferative inhibition and senescence of H1299 cells by PTX in our study.Significance: Our study demonstrates that the short-carbon chain C2-ceramide can effectively sensitize PTX-induced senescence of H1299 cells via both p21(waf1/cip1)- and p16(ink4)-independent pathways. (C) 2010 Elsevier Inc. All rights reserved.