NAD(P)H:Quinone Oxidoreductase-1 Expression Sensitizes Malignant Melanoma Cells to the HSP90 Inhibitor 17-AAG.
NAD(P)H:Quinone Oxidoreductase-1 Expression Sensitizes Malignant Melanoma Cells to the HSP90 Inhibitor 17-AAG.
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DOI：
10.1371/journal.pone.0153181
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Maesawa C
中科院分区：
文献类型：
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作者：
Kasai S;Arakawa N;Okubo A;Shigeeda W;Yasuhira S;Masuda T;Akasaka T;Shibazaki M;Maesawa C
KEAP 1-NRF 2通路通过转录诱导与抗氧化剂合成和解毒相关的基因来调节细胞氧化还原稳态。以前，我们报道了KEAP 1突变在人黑色素瘤中引起组成性NRF 2激活和对顺铂（CDDP）和达卡巴嗪（DTIC）的耐药。本研究的目的是阐明HSP 90抑制剂17-AAG是否能有效地消除KEAP 1突变的黑色素瘤，因为NRF 2靶基因NQO 1是17-AAG生物活化的关键酶。在有或没有KEAP 1突变的黑色素瘤和非小细胞肺癌细胞系中，NQO 1表达和17-AAG敏感性呈负相关。尽管存在野生型KEAP 1，但NQO 1在正常黑素细胞和几种黑素瘤细胞系中高度表达，并且NQO 1表达依赖于NRF 2活化。由于CDDP或DTIC产生活性氧物质激活NRF 2，我们确定这些药物是否会使NQO 1低的黑色素瘤细胞对17-AAG敏感。在五分之四的NQO 1低细胞系中检测到17-AAG和CDDP组合的协同细胞毒性，但在具有KEAP 1突变的细胞系中未检测到。这些数据表明，17-AAG可能是一个潜在的化疗药物与KEAP 1突变或NQO 1表达的黑色素瘤。
The KEAP1-NRF2 pathway regulates cellular redox homeostasis by transcriptional induction of genes associated with antioxidant synthesis and detoxification in response to oxidative stress. Previously, we reported that KEAP1 mutation elicits constitutive NRF2 activation and resistance to cisplatin (CDDP) and dacarbazine (DTIC) in human melanomas. The present study was conducted to clarify whether an HSP90 inhibitor, 17-AAG, efficiently eliminates melanoma with KEAP1 mutation, as the NRF2 target gene, NQO1, is a key enzyme in 17-AAG bioactivation. In melanoma and non-small cell lung carcinoma cell lines with or without KEAP1 mutations, NQO1 expression and 17-AAG sensitivity are inversely correlated. NQO1 is highly expressed in normal melanocytes and in several melanoma cell lines despite the presence of wild-type KEAP1, and the NQO1 expression is dependent on NRF2 activation. Because either CDDP or DTIC produces reactive oxygen species that activate NRF2, we determined whether these agents would sensitize NQO1-low melanoma cells to 17-AAG. Synergistic cytotoxicity of the 17-AAG and CDDP combination was detected in four out of five NQO1-low cell lines, but not in the cell line with KEAP1 mutation. These data indicate that 17-AAG could be a potential chemotherapeutic agent for melanoma with KEAP1 mutation or NQO1 expression.