Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma.
Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma.
复制标题
顺序去代替他和卡铂处理增加了DNA修复蛋白XPC，增加了凋亡并减少黑色素瘤的增殖。
DOI：
10.1186/s12885-018-4010-9
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发表时间：
2018-01-26
期刊：
影响因子：
3.8
通讯作者：
Bowden NA
中科院分区：
文献类型：
--
作者：
Budden T;van der Westhuizen A;Bowden NA
黑色素瘤有两个关键特征，紫外线诱导突变的过度表达和对DNA破坏化疗药物的耐药性。这两个特征可能是由于核苷酸切除修复途径，特别是DNA损伤检测分支，全球基因组修复(GGR)的功能障碍造成的。在黑色素瘤中，关键的GGR成分XPC对DNA损伤没有反应，这种缺乏反应的原因还没有被调查。在这项研究中，我们研究了甲基化在黑色素瘤XPC减少中的作用。为了减少甲基化和诱导DNA损伤，用地西他滨和卡铂分别和顺序处理黑色素瘤细胞系。检测全球DNA甲基化水平、XPC mRNA和蛋白表达及XPC启动子甲基化。并对细胞凋亡率、细胞增殖率和衰老进行了定量研究。XPC siRNA用于确定所看到的反应依赖于XPC诱导。大剂量地西他滨治疗导致了包括XPC CpG岛海岸在内的整体去甲基化，并显著增加了XPC mRNA的表达。较低的临床相关剂量的地西他滨也导致了包括CpG岛海岸在内的全球去甲基化，并在50%的细胞系中诱导了XPC。在接受测试的黑色素瘤细胞株中，地西他滨和破坏DNA的卡铂治疗导致75%的黑色素瘤细胞株XPC表达显著增加。与卡铂单独治疗相比，联合序贯治疗还导致75%的细胞系有更大的凋亡反应，并显著减缓细胞增殖，一些黑色素瘤细胞系进入衰老。使用siRNA抑制增加的XPC有很小但显著的负面影响，表明XPC在顺序地西他滨和卡铂的反应中起部分作用。使用地西他滨去甲基化可增加序贯卡铂治疗后的XPC和细胞凋亡率。这些结果证实，作为黑色素瘤的联合治疗，地西他滨和卡铂的序贯治疗需要进一步的研究。本文的在线版本(10.1186/s12885-0184010-9)包含向授权用户提供的补充材料。
Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma. To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction. Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin. Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma. The online version of this article (10.1186/s12885-018-4010-9) contains supplementary material, which is available to authorized users.
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