Regulation of pancreatic cancer growth by superoxide
Regulation of pancreatic cancer growth by superoxide
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DOI：
10.1002/mc.21891
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发表时间：
2013-07-01
影响因子：
4.6
通讯作者：
Cullen, Joseph J.
中科院分区：
文献类型：
--
作者：
Du, Juan;Nelson, Elke S.;Cullen, Joseph J.
K-ras突变已在高达95%的胰腺癌中被发现，这表明它们在分子发病机制中起着关键作用。K-ras癌基因在原来源于正常胰腺（H6c7）的永生化人胰腺导管上皮细胞系中表达，诱导小鼠癌的形成。我们假设K-ras癌基因与非线粒体产生的超氧化物（O2）增加有关。-)，可能参与调节促进肿瘤进展的细胞生长。在H6c7细胞系及其衍生物H6c7 - er- kras +（表达K-ras癌基因的H6c7细胞）和H6c7 - er- krast（表达K-ras癌基因的致瘤性H6c7细胞）中，表达K-ras的细胞系氢乙胺荧光增加。Western blots和活性氧解毒酶活性测定。-在这些细胞系中是相似的，这表明氢乙胺荧光的增加不是由于抗氧化能力的下降。确定氧含量升高的可能非线粒体来源。-， Western分析显示，NADPH氧化酶-2 （NOX2）在H6c7细胞中缺失，但在表达K-ras的H6c7细胞系和其他胰腺癌细胞系中存在。抑制NOX2可降低氢乙胺荧光和克隆存活率。此外，在含有K-ras癌基因的细胞系中，超氧化物歧化酶的过度表达可以解毒非线粒体来源的O2。-，然后用小分子O2处理。-清道夫Tempol，也降低氢乙胺荧光，抑制克隆生存和抑制肿瘤生长。因此,O2。-由NOX2与K-ras在胰腺癌细胞中产生，可能调节胰腺癌细胞的生长。(c) 2012 Wiley期刊有限公司
K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Expression of K-ras oncogene in an immortalized human pancreatic ductal epithelial cell line, originally derived from normal pancreas (H6c7), induced the formation of carcinoma in mice. We hypothesized that K-ras oncogene correlates with increased non-mitochondrial-generated superoxide (O2.-), which could be involved in regulating cell growth contributing to tumor progression. In the H6c7 cell line and its derivatives, H6c7er-Kras+ (H6c7 cells expressing K-ras oncogene), and H6c7eR-KrasT (tumorigenic H6c7 cells expressing K-ras oncogene), there was an increase in hydroethidine fluorescence in cell lines that express K-ras. Western blots and activity assays for the antioxidant enzymes that detoxify O2.- were similar in these cell lines suggesting that the increase in hydroethidine fluorescence was not due to decreased antioxidant capacity. To determine a possible non-mitochondrial source of the increased levels of O2.-, Western analysis demonstrated the absence of NADPH oxidase-2 (NOX2) in H6c7 cells but present in the H6c7 cell lines expressing K-ras and other pancreatic cancer cell lines. Inhibition of NOX2 decreased hydroethidine fluorescence and clonogenic survival. Furthermore, in the cell lines with the K-ras oncogene, overexpression of superoxide dismutases that detoxify non-mitochondrial sources of O2.-, and treatment with the small molecule O2.- scavenger Tempol, also decreased hydroethidine fluorescence, inhibited clonogenic survival and inhibited growth of tumor xenografts. Thus, O2.- produced by NOX2 in pancreatic cancer cells with K-ras, may regulate pancreatic cancer cell growth. (c) 2012 Wiley Periodicals, Inc.