Decreased levels of baseline and drug-induced tubulin polymerisation are hallmarks of resistance to taxanes in ovarian cancer cells and are associated with epithelial-to-mesenchymal transition.
Decreased levels of baseline and drug-induced tubulin polymerisation are hallmarks of resistance to taxanes in ovarian cancer cells and are associated with epithelial-to-mesenchymal transition.
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DOI：
10.1038/bjc.2017.102
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发表时间：
2017-05-09
影响因子：
8.8
通讯作者：
Sikic BI
中科院分区：
文献类型：
--
作者：
Duran GE;Wang YC;Moisan F;Francisco EB;Sikic BI
ABCB 1表达在卵巢癌的临床中并不常见，因此我们研究了紫杉烷类耐药的非MDR机制。我们从人卵巢癌细胞系A2780/1A9、ES-2、MES-OV和OVCAR-3中建立了8种紫杉烷耐药变异体，通过紫杉醇或多西他赛选择，并通过转运抑制剂伐司泊达进行反选择。非MDR紫杉烷类耐药与细胞内紫杉烷含量降低（与亲本对照相比）和对其他微管稳定药物的交叉耐药相关。伴随细胞内长春碱增加，观察到对解聚剂（长春花生物碱和秋水仙碱）的附带敏感性。这些变体表现出显着减少，在基础微管蛋白聚合物和微管蛋白聚合反应紫杉烷曝光。TUBB3含量在8种变体中的6种中增加。我们分析了亲本系和抗性变体的基因表达，并确定了转录组学特征，其中两个高度重要的网络围绕FN1和CDKN1A构建，与细胞粘附，细胞间信号传导和细胞周期调控相关。miR-200家族成员miR-200 b和miR-200 c在耐药细胞中下调，与上皮向间质转化（EMT）相关，VIM、FN 1、MMP 2和/或MMP 9增加。这些改变可以作为预测紫杉烷对卵巢癌有效性的生物标志物，并应被视为治疗靶点。
ABCB1 expression is uncommon in ovarian cancers in the clinical setting so we investigated non-MDR mechanisms of resistance to taxanes. We established eight taxane-resistant variants from the human ovarian carcinoma cell lines A2780/1A9, ES-2, MES-OV and OVCAR-3 by selection with paclitaxel or docetaxel, with counter-selection by the transport inhibitor valspodar. Non-MDR taxane resistance was associated with reduced intracellular taxane content compared to parental controls, and cross-resistance to other microtubule stabilising drugs. Collateral sensitivity to depolymerising agents (vinca alkaloids and colchicine) was observed with increased intracellular vinblastine. These variants exhibited marked decreases in basal tubulin polymer and in tubulin polymerisation in response to taxane exposure. TUBB3 content was increased in 6 of the 8 variants. We profiled gene expression of the parental lines and resistant variants, and identified a transcriptomic signature with two highly significant networks built around FN1 and CDKN1A that are associated with cell adhesion, cell-to-cell signalling, and cell cycle regulation. miR-200 family members miR-200b and miR-200c were downregulated in resistant cells, associated with epithelial to mesenchymal transition (EMT), with increased VIM, FN1, MMP2 and/or MMP9. These alterations may serve as biomarkers for predicting taxane effectiveness in ovarian cancer and should be considered as therapeutic targets.