Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation.
Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation.
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DOI：
10.18632/oncotarget.9118
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发表时间：
2016-06-07
期刊：
影响因子：
--
通讯作者：
Lee SK
中科院分区：
文献类型：
--
作者：
Aldonza MB;Hong JY;Alinsug MV;Song J;Lee SK
获得性耐药性是有效癌症治疗的主要障碍。III类β-微管蛋白（TUBB 3）的点突变与多药耐药基因ATP结合盒P-糖蛋白（ABCB 1）的显著过表达的相关性已成为许多癌症对微管破坏剂（如紫杉醇（PTX））的耐药机制。然而，在PTX耐药癌症中对一系列结构和功能无关的药物快速产生交叉耐药性的确切潜在机制尚不清楚。我们确定，我们建立的PTX耐药癌细胞显示ABCB 1/ABCC 1相关的交叉耐药化学不同的药物，如5-氟尿嘧啶，多西他赛，顺铂。我们发现TUBB 3的反馈激活可以通过ABCB 1的FOXO 3a依赖性调节来触发，这导致诱导的PTX抗性的加重，并鼓励获得性交叉抗性的多样性。FOXO 3a对P-糖蛋白（P-gp）功能的调控表明ABCB 1的控制涉及甲基化依赖性激活。一致地，FOXO 3a的转录过表达或下调指导TUBB 3的通道控制的蛋白酶降解。功能性PI 3 K/Akt信号传导与多柔比星治疗一起对FOXO 3a活化有紧密响应，其指导FOXO 3a精氨酸超甲基化。此外，我们发现，来自PTX耐药癌细胞的分泌组因子与获得性交叉耐药支持多药耐药（MDR）发展中的P-gp依赖性关联，这有助于FOXO 3a介导的TUBB 3反馈控制。TUBB 3的直接沉默逆转诱导的多重交叉耐药性，减少耐药肿瘤质量，并抑制具有瞬时交叉耐药性的PTX耐药细胞的受损微管稳定性状态。这些发现强调了控制TUBB 3对ABCB 1遗传抑制剂的反应是逆转癌症多药耐药性大量发展的一种机制。
Acquired drug resistance is a primary obstacle for effective cancer therapy. The correlation of point mutations in class III β-tubulin (TUBB3) and the prominent overexpression of ATP-binding cassette P-glycoprotein (ABCB1), a multidrug resistance gene, have been protruding mechanisms of resistance to microtubule disruptors such as paclitaxel (PTX) for many cancers. However, the precise underlying mechanism of the rapid onset of cross-resistance to an array of structurally and functionally unrelated drugs in PTX-resistant cancers has been poorly understood. We determined that our established PTX-resistant cancer cells display ABCB1/ABCC1-associated cross-resistance to chemically different drugs such as 5-fluorouracil, docetaxel, and cisplatin. We found that feedback activation of TUBB3 can be triggered through the FOXO3a-dependent regulation of ABCB1, which resulted in the accentuation of induced PTX resistance and encouraged multiplicity in acquired cross-resistance. FOXO3a-directed regulation of P-glycoprotein (P-gp) function suggests that control of ABCB1 involves methylation-dependent activation. Consistently, transcriptional overexpression or downregulation of FOXO3a directs inhibitor-controlled protease-degradation of TUBB3. The functional PI3K/Akt signaling is tightly responsive to FOXO3a activation alongside doxorubicin treatment, which directs FOXO3a arginine hypermethylation. In addition, we found that secretome factors from PTX-resistant cancer cells with acquired cross-resistance support a P-gp-dependent association in multidrug resistance (MDR) development, which assisted the FOXO3a-mediated control of TUBB3 feedback. The direct silencing of TUBB3 reverses induced multiple cross-resistance, reduces drug-resistant tumor mass, and suppresses the impaired microtubule stability status of PTX-resistant cells with transient cross-resistance. These findings highlight the control of the TUBB3 response to ABCB1 genetic suppressors as a mechanism to reverse the profuse development of multidrug resistance in cancer.
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影响因子：
8.8
作者：
El-Khoury, V.;Breuzard, G.;Fourre, N.;Dufer, J.
通讯作者：
Dufer, J.
影响因子：
5.7
作者：
Hui, Rosaline C-Y.;Francis, Richard E.;Lam, Eric W-F.
通讯作者：
Lam, Eric W-F.
影响因子：
5.7
作者：
Hari, M;Loganzo, F;Greenberger, LM
通讯作者：
Greenberger, LM
影响因子：
--
作者：
Bae SY;Hong JY;Lee HJ;Park HJ;Lee SK
通讯作者：
Lee SK
DOI：
10.1186/1756-9966-30-93
发表时间：
2011-10-05
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Kadoyama K;Kuwahara A;Yamamori M;Brown JB;Sakaeda T;Okuno Y
通讯作者：
Okuno Y