Cross-talk between signalling pathways and the multidrug resistant protein MDR-1.
Cross-talk between signalling pathways and the multidrug resistant protein MDR-1.
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DOI：
10.1054/bjoc.2001.2044
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发表时间：
2001-10-19
影响因子：
8.8
通讯作者：
Wolf, C R
中科院分区：
文献类型：
--
作者：
Ding, S;Chamberlain, M;McLaren, A;Goh, L;Duncan, I;Wolf, C R
多药耐药蛋白MDR-1与多种抗癌药物的耐药性有关。紫杉醇是这种转运系统的底物，用于治疗多种人类恶性肿瘤，包括肺癌、乳腺癌和卵巢癌。我们已经产生了一系列的卵巢细胞株耐药这种化合物，所有这些都过表达MDR-1通过基因扩增。我们提出了新的证据，组成性激活的ERK 1/2 MAP激酶通路也观察到，虽然活性JNK和p38的水平保持不变。使用UO 126或PD 098059抑制ERK 1/2 MAP激酶途径使紫杉醇耐药细胞重新敏感至少20倍。重要的是，当Mdr-1 cDNA在野生型细胞系中稳定表达以产生高度紫杉醇耐药的亚系1847/MDR 5时，ERK 1/2 MAP激酶再次被激活。这一结果表明，紫杉醇耐药株中信号通路活性的增加直接归因于MDR-1过表达，而不是由于紫杉醇本身的作用。此外，我们证明了用LY 294002抑制P13 K通路使表达MDR-1的1847/TX0.5细胞和1847/MDR 5细胞至少10倍敏感，但对野生型细胞没有影响。这一发现表明，这一途径也可能在紫杉醇耐药性的产生中发挥作用。© 2001年癌症研究运动http：www.bjcancer.com
The multidrug resistant protein MDR-1 has been associated with the resistance to a wide range of anti-cancer drugs. Taxol is a substrate for this transporter system and is used in the treatment of a wide range of human malignancies including lung, breast and ovarian cancer. We have generated a series of ovarian cell lines resistant to this compound, all of which overexpress MDR-1 through gene amplification. We present novel evidence that a constitutive activation of the ERK1/2 MAP kinase pathway was also observed although the level of active JNK and p38 remained unchanged. Inhibition of the ERK1/2 MAP kinase pathway using UO126 or PD098059 re-sensitised the Taxol resistant cells at least 20-fold. Importantly, when Mdr-1 cDNA was stably expressed in the wild-type cell line to generate a highly Taxol-resistant sub-line, 1847/MDR5, ERK1/2 MAP kinases again became activated. This result demonstrated that the increased activity of the signalling pathway in the Taxol-resistant lines was directly attributable to MDR-1 overexpression and was not due to the effects of Taxol itself. Additionally, we demonstrated that inhibition of the P13K pathway with LY294002 sensitised the MDR-1-expressing 1847/TX0.5 cells and 1847/MDR5 cells at least 10-fold but had no effect in the wild-type cells. This finding suggests a possible role for this pathway, also, in the generation of resistance to Taxol. © 2001 Cancer Research Campaign http://www.bjcancer.com