Mutations in the mitochondrial genome confer resistance of cancer cells to anticancer drugs
Mutations in the mitochondrial genome confer resistance of cancer cells to anticancer drugs
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DOI：
10.1111/j.1349-7006.2009.01238.x
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发表时间：
2009-09
期刊：
影响因子：
5.7
通讯作者：
S. Mizutani;Y. Miyato;Yujiro Shidara;S. Asoh;A. Tokunaga;T. Tajiri;S. Ohta
中科院分区：
文献类型：
--
作者：
S. Mizutani;Y. Miyato;Yujiro Shidara;S. Asoh;A. Tokunaga;T. Tajiri;S. Ohta
大多数癌细胞在线粒体基因组中存在同质体细胞突变。我们在这里展示了线粒体DNA （mtDNA）的突变与抗癌药物耐受性有关。我们构建了几个来自人类胰腺癌细胞系CFPAC‐1和CAPAN‐2以及健康个体的mtDNA的反线粒体杂交（cybrids）。这些杂交体含有不同的线粒体基因组，但具有共同的核背景。我们在体外将突变型和野生型细胞系暴露于星孢素、5 -氟尿嘧啶和顺铂中，比较了突变型和野生型细胞系对细胞凋亡诱导试剂和抗癌药物的耐药性，发现所有突变型细胞系对细胞凋亡诱导和抗癌药物的耐药性都比野生型细胞系强。接下来，我们将突变型和野生型杂交体移植到裸鼠体内产生肿瘤。当给予5 -氟尿嘧啶和顺铂时，突变型细胞系衍生的肿瘤在抑制肿瘤生长和诱导大量细胞凋亡方面比野生型细胞系衍生的肿瘤更具抗性。为了证实突变体对抗癌药物的耐受性，我们将突变体和野生型杂交体按1:1的比例移植到裸鼠体内，观察药物对突变体和野生型mtDNA比例漂移的影响。突变的mtDNA表现出更好的存活率，表明突变的杂交体对抗癌药物具有更强的耐药性。因此，我们提出线粒体基因组突变是癌症患者使用抗癌药物时影响预后的潜在靶点。（癌症科学2009；100:1680-1687）
The majority of cancer cells harbor homoplasmic somatic mutations in the mitochondrial genome. We show here that mutations in mitochondrial DNA (mtDNA) are responsible for anticancer drug tolerance. We constructed several trans‐mitochondrial hybrids (cybrids) with mtDNA derived from human pancreas cancer cell lines CFPAC‐1 and CAPAN‐2 as well as from healthy individuals. These cybrids contained the different mitochondrial genomes with the common nuclear background. We compared the mutant and wild‐type cybrids for resistance against an apoptosis‐inducing reagent and anticancer drugs by exposing the cybrids to staurosporine, 5‐fluorouracil, and cisplatin in vitro, and found that all mutant cybrids were more resistant to the apoptosis‐inducing and anticancer drugs than wild‐type cybrids. Next, we transplanted mutant and wild‐type cybrids into nude mice to generate tumors. Tumors derived from mutant cybrids were more resistant than those from wild‐type cybrids in suppressing tumor growth and inducing massive apoptosis when 5‐fluorouracil and cisplatin were administered. To confirm the tolerance of mutant cybrids to anticancer drugs, we transplanted a mixture of mutant and wild‐type cybrids at a 1:1 ratio into nude mice and examined the effect by the drugs on the drift of the ratio of mutant and wild‐type mtDNA. The mutant mtDNA showed better survival, indicating that mutant cybrids were more resistant to the anticancer drugs. Thus, we propose that mutations in the mitochondrial genome are potential targets for prognosis in the administration of anticancer drugs to cancer patients. (Cancer Sci 2009; 100: 1680–1687)