E2F1 confers anticancer drug resistance by targeting ABC transporter family members and Bcl-2 via the p73/DNp73-miR-205 circuitry.
E2F1 confers anticancer drug resistance by targeting ABC transporter family members and Bcl-2 via the p73/DNp73-miR-205 circuitry.
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DOI：
10.4161/cc.21476
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发表时间：
2012-08-15
期刊：
影响因子：
--
通讯作者：
Pützer BM
中科院分区：
文献类型：
--
作者：
Alla V;Kowtharapu BS;Engelmann D;Emmrich S;Schmitz U;Steder M;Pützer BM
肿瘤对化疗药物的耐药性是导致治疗失败的主要原因，并导致肿瘤复发和转移。E2 F1通过其激活p53/p73死亡途径的能力是响应于DNA损伤的细胞凋亡的强诱导剂。然而，最近的证据表明，在晚期恶性黑色素瘤中异常表达的E2 F1与拮抗性p73家族成员一起驱动癌症进展。研究负责失调E2 F1失去其凋亡功能的机制，我们寻找原发性和晚期临床肿瘤阶段的基因组特征，以预测与侵袭性黑色素瘤细胞的凋亡抗性和存活相关的下游效应子。我们将miR-205鉴定为p73的特异性靶点，并发现在遗传毒性应激后，其表达被内源性DNp 73充分消除。值得注意的是，转移性细胞可以通过在p73耗尽的细胞中选择性敲低DNp 73或过表达miR-205而从耐药性中拯救出来，导致体内细胞凋亡增加和肿瘤生长减少。我们的数据描绘了一个自动调节回路，涉及高水平的E2 F1和DNp 73下调miR-205，这反过来又控制E2 F1的积累。最后，通过消除miR-205对Bcl-2和与多药耐药和恶性进展相关的ATP结合盒转运蛋白A2（ABCA 2）和A5（ABCA 5）表达的抑制作用，介导了与该基因签名相关的耐药性。这些结果将E2 F1-p73/DNp 73-miR-205轴定义为化学抗性的关键机制，因此，作为转移预防的靶点。
Resistance to anti-neoplastic agents is the major cause of therapy failure, leading to disease recurrence and metastasis. E2F1 is a strong inducer of apoptosis in response to DNA damage through its capacity to activate p53/p73 death pathways. Recent evidence, however, showed that E2F1, which is aberrantly expressed in advanced malignant melanomas together with antagonistic p73 family members, drives cancer progression. Investigating mechanisms responsible for dysregulated E2F1 losing its apoptotic function, we searched for genomic signatures in primary and late clinical tumor stages to allow the prediction of downstream effectors associated with apoptosis resistance and survival of aggressive melanoma cells. We identified miR-205 as specific target of p73 and found that upon genotoxic stress, its expression is sufficiently abrogated by endogenous DNp73. Significantly, metastatic cells can be rescued from drug resistance by selective knockdown of DNp73 or overexpression of miR-205 in p73-depleted cells, leading to increased apoptosis and the reduction of tumor growth in vivo. Our data delineate an autoregulatory circuit, involving high levels of E2F1 and DNp73 to downregulate miR-205, which, in turn, controls E2F1 accumulation. Finally, drug resistance associated to this genetic signature is mediated by removing the inhibitory effect of miR-205 on the expression of Bcl-2 and the ATP-binding cassette transporters A2 (ABCA2) and A5 (ABCA5) related to multi-drug resistance and malignant progression. These results define the E2F1-p73/DNp73-miR-205 axis as a crucial mechanism for chemoresistance and, thus, as a target for metastasis prevention.
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DOI：
10.1084/jem.191.6.1005
发表时间：
2000-03-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Halaban R;Cheng E;Smicun Y;Germino J
通讯作者：
Germino J
影响因子：
11.2
作者：
Iorio, MV;Ferracin, M;Croce, CM
通讯作者：
Croce, CM
影响因子：
5.7
作者：
Millour J;de Olano N;Horimoto Y;Monteiro LJ;Langer JK;Aligue R;Hajji N;Lam EW
通讯作者：
Lam EW
影响因子：
11.2
作者：
Sempere, Lorenzo F.;Christensen, Mette;Cole, Charles N.
通讯作者：
Cole, Charles N.
影响因子：
12.4
作者：
John, K.;Alla, V.;Puetzer, B. M.
通讯作者：
Puetzer, B. M.