Acquisition of resistance of pancreatic cancer cells to 2-methoxyestradiol is associated with the upregulation of manganese superoxide dismutase.
Acquisition of resistance of pancreatic cancer cells to 2-methoxyestradiol is associated with the upregulation of manganese superoxide dismutase.
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DOI：
10.1158/1541-7786.mcr-11-0378
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Du Y
中科院分区：
文献类型：
--
作者：
Zhou J;Du Y
癌细胞对抗癌药物或电离辐射（IR）的获得性抗性是癌症治疗的主要障碍之一。胰腺癌是一种特殊的侵袭性癌症，并且在这种癌症中获得性耐药性是常见的。活性氧簇（ROS）在细胞凋亡中发挥着重要作用，细胞凋亡是放疗或化疗诱导细胞杀伤的关键机制。线粒体是细胞内ROS的主要来源。因此，参与ROS产生或清除的线粒体蛋白表达的改变可能与癌细胞对放射治疗或化学治疗的抗性密切相关。在本研究中，我们通过将胰腺癌细胞暴露于增加浓度的ROS诱导的抗癌化合物2-甲氧基乙烯（2-ME）超过三个月来产生稳定的细胞系。所得细胞系显示出对2-ME的强抗性，并且含有升高水平的ROS。然后，我们使用比较蛋白质组学方法来分析亲本和抗性细胞之间线粒体蛋白质的差异表达。在抗性细胞中被鉴定为上调的一种蛋白质是锰超氧化物歧化酶（SOD 2），这是一种将超氧化物自由基转化为过氧化氢的线粒体蛋白。SOD 2的沉默使抗性细胞对2-ME重新敏感，SOD 2的过表达导致亲本细胞对2-ME产生抗性。此外，2-ME耐药细胞也表现出抵抗IR。我们的研究结果表明，上调SOD 2表达是胰腺癌细胞获得抵抗ROS诱导，抗癌药物，并可能也IR的一个重要机制。
Acquired resistance of cancer cells to anti-cancer drugs or ionizing radiation (IR) is one of the major obstacles in cancer treatment. Pancreatic cancer is an exceptional aggressive cancer, and acquired drug resistance in this cancer is common. Reactive oxygen species (ROS) play an essential role in cell apoptosis, which is a key mechanism by which radio- or chemo-therapy induces cell killing. Mitochondria are the major source of ROS in cells. Thus, alterations in the expression of mitochondrial proteins involved in ROS production or scavenging may be closely linked to the resistance of cancer cells to radio- or chemo-therapy. In the present study, we generated a stable cell line by exposing pancreatic cancer cells to increasing concentrations of ROS-inducing, anti-cancer compound 2-methoxyestradiol (2-ME) over a three month period. The resulting cell line showed strong resistance to 2-ME and contained an elevated level of ROS. We then used a comparative proteomics method to profile the differential expression of mitochondrial proteins between the parental and the resistant cells. One protein identified to be upregulated in the resistant cells was manganese superoxide dismutase (SOD2), a mitochondrial protein that converts superoxide radicals to hydrogen peroxides. Silencing of SOD2 re-sensitized the resistant cells to 2-ME, and overexpression of SOD2 led the parental cells to 2-ME resistance. In addition, the 2-ME-resistant cells also demonstrated resistance to IR. Our results suggest that upregulation of SOD2 expression is an important mechanism by which pancreatic cancer cells acquire resistance to ROS-inducing, anti-cancer drugs, and potentially also to IR.