ABCF2, an Nrf2 target gene, contributes to cisplatin resistance in ovarian cancer cells.
ABCF2, an Nrf2 target gene, contributes to cisplatin resistance in ovarian cancer cells.
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ABCF2 是 Nrf2 靶基因，有助于卵巢癌细胞对顺铂产生耐药性。
DOI：
10.1002/mc.22615
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发表时间：
2017-06
影响因子：
4.6
通讯作者：
Yi X
中科院分区：
文献类型：
--
作者：
Bao L;Wu J;Dodson M;Rojo de la Vega EM;Ning Y;Zhang Z;Yao M;Zhang DD;Xu C;Yi X
以前，我们已经证明NRF 2在介导卵巢癌顺铂耐药中起着关键作用。为了进一步探索NRF 2依赖性顺铂耐药的机制，我们分别在亲本和顺铂耐药的人卵巢癌细胞中稳定过表达或敲低NRF 2。然后对这两对稳定的细胞系进行微阵列分析，其中我们鉴定了18个推定的NRF 2靶基因。在这些基因中，ABCF 2，转运蛋白ABC超家族的胞质成员，以前曾报道有助于卵巢透明细胞癌的化疗耐药性。对ABCF 2的详细分析揭示了其启动子区域中的功能性抗氧化反应元件（ARE），确立ABCF 2为NRF 2靶基因。接下来，我们使用我们的稳定卵巢癌细胞系研究了ABCF 2在NRF 2介导的顺铂耐药性中的作用。与对照细胞系相比，含有高水平ABCF 2的NRF 2过表达细胞系对顺铂诱导的细胞凋亡更具抗性;而具有低水平ABCF 2的NRF 2敲低细胞系对顺铂治疗比其对照细胞系更敏感。此外，ABCF 2在亲代细胞中的瞬时过表达减少了顺铂处理后的细胞凋亡并增加了细胞活力。相反，使用特异性siRNA敲低ABCF 2显著增加了顺铂耐药细胞的凋亡，降低了顺铂治疗的细胞活力。这些数据表明，新的NRF 2靶基因ABCF 2在卵巢癌顺铂耐药中起着关键作用，靶向ABCF 2可能是提高化疗效率的新策略。
Previously, we have demonstrated that NRF2 plays a key role in mediating cisplatin resistance in ovarian cancer. To further explore the mechanism underlying NRF2-dependent cisplatin resistance, we stably overexpressed or knocked down NRF2 in parental and cisplatin-resistant human ovarian cancer cells, respectively. These two pairs of stable cell lines were then subjected to microarray analysis, where we identified 18 putative NRF2 target genes. Among these genes, ABCF2, a cytosolic member of the ABC superfamily of transporters, has previously been reported to contribute to chemoresistance in clear cell ovarian cancer. A detailed analysis on ABCF2 revealed a functional antioxidant response element (ARE) in its promoter region, establishing ABCF2 as an NRF2 target gene. Next, we investigated the contribution of ABCF2 in NRF2-mediated cisplatin resistance using our stable ovarian cancer cell lines. The NRF2-overexpressing cell line, containing high levels of ABCF2, was more resistant to cisplatin-induced apoptosis compared to its control cell line; whereas the NRF2 knockdown cell line with low levels of ABCF2, was more sensitive to cisplatin treatment than its control cell line. Furthermore, transient overexpression of ABCF2 in the parental cells decreased apoptosis and increased cell viability following cisplatin treatment. Conversely, knockdown of ABCF2 using specific siRNA notably increased apoptosis and decreased cell viability in cisplatin-resistant cells treated with cisplatin. This data indicates that the novel NRF2 target gene, ABCF2, plays a critical role in cisplatin resistance in ovarian cancer, and that targeting ABCF2 may be a new strategy to improve chemotherapeutic efficiency.
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