NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response.
NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response.
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DOI：
10.1038/onc.2011.290
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发表时间：
2012-02-23
期刊：
影响因子：
8
通讯作者：
Yang, J-M
中科院分区：
文献类型：
--
作者：
Zhang, Y.;Cheng, Y.;Ren, X.;Zhang, L.;Yap, K. L.;Wu, H.;Patel, R.;Liu, D.;Qin, Z-H;Shih, I-M;Yang, J-M
伏隔核-1(NAC1)是BTB/POZ基因家族中的一种核因子，在肿瘤细胞的增殖、生长和化疗耐药中起重要作用。然而，NAC1如何导致耐药性的潜在机制在很大程度上仍不清楚。我们在这里报道了自噬参与了NAC1介导的对顺铂的耐药性，顺铂是一种治疗卵巢癌的常用化疗药物。我们发现顺铂治疗引起卵巢癌细胞株A2780、OVCAR3和SKOV3自噬的激活。我们进一步证明，通过RNAi敲除NAC1或通过诱导仅包含BTB/POZ结构域的NAC1缺失突变体的表达来灭活NAC1显著抑制顺铂诱导的自噬，导致顺铂细胞毒性增加。此外，NAC1基因敲除或失活可抑制细胞自噬和增敏顺铂，并可诱导细胞凋亡。为了证实NAC1抑制对顺铂细胞毒性的增敏作用归因于抑制自噬，我们研究了自噬抑制剂3-MA和氯喹以及针对Beclin 1或ATG5的siRNAs对顺铂细胞毒性的影响。用3-MA、氯喹或Beclin 1和ATG5靶向的siRNA处理SKOV3、A2780和OVCAR3细胞也能增强对顺铂的敏感性，表明抑制自噬确实使肿瘤细胞对顺铂更敏感。NAC1对自噬的调节是通过高迁移率族蛋白1(HMGB1)介导的，因为NAC1的功能状态与HMGB1的表达、转位和释放有关。我们的研究结果不仅揭示了决定顺铂敏感性的新机制，而且还确认NAC1是一种新的自噬调节因子。因此，NAC1介导的自噬可能成为提高顺铂治疗卵巢癌和其他类型恶性肿瘤疗效的新靶点。
Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is known to play important roles in proliferation and growth of tumor cells and in chemotherapy resistance. Yet, the mechanisms underlying how NAC1 contributes to drug resistance remain largely unclear. We reported here that autophagy was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. We found that treatment with cisplatin caused an activation of autophagy in ovarian cancer cell lines, A2780, OVCAR3, and SKOV3. We further demonstrated that knockdown of NAC1 by RNAi or inactivation of NAC1 by inducing the expression of a NAC1 deletion mutant that contains only the BTB/POZ domain significantly inhibited the cisplatin-induced autophagy, resulting in increased cisplatin cytotoxicity. Moreover, inhibition of autophagy and sensitization to cisplatin by NAC1 knockdown or inactivation were accompanied by induction of apoptosis. To confirm that the sensitizing effect of NAC1 inhibition on the cytotoxicity of cisplatin was attributed to suppression of autophagy, we assessed the effects of the autophagy inhibitors, 3-MA and chloroquine, and siRNAs targeting beclin 1 or Atg5, on the cytotoxicity of cisplatin. Treatment with 3-MA, chloroquine or beclin 1 and Atg5-targeted siRNA also enhanced the sensitivity of SKOV3, A2780 and OVCAR3 cells to cisplatin, indicating that suppression of autophagy indeed renders tumor cells more sensitive to cisplatin. Regulation of autophagy by NAC1 was mediated via high mobility group box1 (HMGB1), as the functional status of NAC1 was associated with the expression, translocation and release of HMGB1. The results of our study not only revealed a new mechanism determining cisplatin sensitivity, but also identified NAC1 as a novel regulator of autophagy. Thus, the NAC1- mediated autophagy may be exploited as a new target for enhancing the efficacy of cisplatin against ovarian cancer and other types of malignancies.
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影响因子：
3.7
作者：
Cheng Y;Li H;Ren X;Niu T;Hait WN;Yang J
通讯作者：
Yang J
影响因子：
64.8
作者：
Mueller, Franz-Josef;Laurent, Louise C.;Kostka, Dennis;Ulitsky, Igor;Williams, Roy;Lu, Christina;Park, In-Hyun;Rao, Mahendra S.;Shamir, Ron;Schwartz, Philip H.;Schmidt, Nils O.;Loring, Jeanne F.
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影响因子：
64.5
作者：
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Orkin, Stuart H.
影响因子：
5.3
作者：
Harhaji-Trajkovic L;Vilimanovich U;Kravic-Stevovic T;Bumbasirevic V;Trajkovic V
通讯作者：
Trajkovic V
影响因子：
12.4
作者：
Thorburn, J.;Horita, H.;Redzic, J.;Hansen, K.;Frankel, A. E.;Thorburn, A.
通讯作者：
Thorburn, A.