Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability
Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability
复制标题
DOI：
10.3858/emm.2008.40.1.109
复制
发表时间：
2008-02-29
影响因子：
12.8
通讯作者：
Park, Seung-Yoon
中科院分区：
文献类型：
--
作者：
Lee, Wan;Choi, Hyo-Im;Park, Seung-Yoon
线粒体DNA （mtDNA）的突变和减少已被认为是致癌的因素。然而，mtDNA的缺失是否会引起癌细胞的多药耐药还没有得到充分的研究。为了阐明细胞mtDNA含量与耐药之间的关系，我们对HCT-8结肠癌细胞进行了研究，发现细胞mtDNA和ATP含量显著降低，同时mtDNA编码的mrna缺失。mtDNA缺失的细胞表现出抗癌药物敏感性降低和积累，表明mtDNA缺失可能在HCT-8细胞中形成多药耐药（MDR）表型。我们发现MDR1 mRNA及其翻译产物p -糖蛋白在mtdna缺失的细胞中表达水平升高，表明mtdna缺失的细胞中抗癌药物敏感性降低和积累可能是由于p -糖蛋白的表达大幅增加。此外，MDR1 mRNA和p -糖蛋白表达的增加是由于mRNA稳定性的增加而不是转录激活。综上所述，这些结果表明mtDNA缺失可以通过mRNA稳定性的增加诱导p -糖蛋白表达的增加，并提示mtDNA缺失在癌细胞中诱导MDR表型中起重要作用。
The mutation and reduction of mitochondrial DNA (mtDNA) have been suggested as factors in the carcinogenesis. However, whether the depletion of mtDNA induces multidrug resistance in cancer cells has not been fully investigated. To elucidate the association of cellular mtDNA content and drug resistance, we generated HCT-8 colon cancer cells which revealed a marked decrease in cellular mtDNA and ATP content, concomitant with a lack of mRNAs encoded by mtDNA. The mtDNA-depleted cells showed a decreased sensitivity and accumulation of anti-cancer drugs, suggesting that mtDNA depletion could develop multidrug resistance (MDR) phenotype in HCT-8 cells. We found that the expression level of MDR1 mRNA and its translated product P-glycoprotein was increased in the mtDNA-depleted cells, indicating that the decrease of sensitivity and accumulation of anti-cancer drug in the mtDNA-depleted cells might be due to a substantial increase in the expression of P-glycoprotein. Furthermore, increased expression of MDR1 mRNA and P-glycoprotein was due to an increase of mRNA stability rather than transcriptional activation. Taken together, these results indicate that mtDNA depletion can induce an increased P-glycoprotein expression via an increase of mRNA stability and suggest that the mtDNA depletion in cancer cells plays an important role in the induction of MDR phenotype.