Cathepsin D and Eukaryotic Translation Elongation Factor 1 as Promising Markers of Cellular Senescence
Cathepsin D and Eukaryotic Translation Elongation Factor 1 as Promising Markers of Cellular Senescence
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DOI：
10.1158/0008-5472.can-08-4042
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发表时间：
2009-06-01
期刊：
影响因子：
11.2
通讯作者：
Lee, Jae-Seon
中科院分区：
文献类型：
--
作者：
Byun, Hae-Ok;Han, Na-Kyung;Lee, Jae-Seon
诱导早衰可能是癌症治疗的一个有前途的策略。然而，缺乏衰老癌细胞的生物标志物。为了鉴定这些生物标志物，我们对MCF 7人乳腺癌细胞进行了比较蛋白质组学分析，这些细胞在电离辐射（IR）的作用下发生细胞衰老。IR诱导的衰老与组织蛋白酶D（CD）的上调和真核翻译延伸因子1 β 2（eEF 1B 2）的下调有关，如Western blot所证实的。另一个延伸因子，真核翻译延伸因子1 α 1（eEF 1A 1），也下调。在HCT 116结肠癌细胞系和H460肺癌细胞系中，IR诱导的衰老与CD和eEF 1（eEF 1A 1和eEF 1B 2）水平的相似变化相关。CD的上调和eEF 1的下调似乎是衰老的特异性，因为它们在过氧化氢或抗癌药物（喜树碱、依托泊苷或50 ng阿霉素）诱导的细胞衰老过程中观察到，但在紫杉醇或10 μ g阿霉素诱导的细胞凋亡或他莫昔芬诱导的自噬过程中观察不到。在复制性衰老和Ras癌基因诱导的衰老过程中观察到CD和eEF 1A 1水平的相同改变。短暂的细胞周期停滞没有改变eEF 1或CD的水平。化学抑制CD（胃酶抑素A）和小干扰RNA介导的敲低CD和eEF 1揭示，这些因素参与细胞增殖。最后，在细胞系中观察到的CD和eEF 1水平的衰老相关改变也在IR暴露的异种移植肿瘤中观察到。这些发现表明CD和eEF 1是检测由各种治疗诱导的细胞衰老的有希望的标志物。[Cancer Res 2009;69（11）：4638-47]
Induction of premature senescence may be a promising strategy for cancer treatment. However, biomarkers for senescent cancer cells are lacking. To identify such biomarkers, we performed comparative proteomic analysis of MCF7 human breast cancer cells undergoing cellular senescence in response to ionizing radiation (IR). IR-induced senescence was associated with up-regulation of cathepsin D (CD) and down-regulation of eukaryotic translation elongation factor 1 beta 2 (eEF1B2), as confirmed by Western blot. The other elongation factor, eukaryotic translation elongation factor 1 alpha 1 (eEF1A1), was also down-regulated. IR-induced senescence was associated with similar changes of CD and eEF1 (eEF1A1 and eEF1B2) levels in the HCT116 colon cancer cell line and the H460 lung cancer cell line. Up-regulation of CD and down-regulation of eEF1 seemed to be specific to senescence, as they were observed during cellular senescence induced by hydrogen peroxide or anticancer drugs (camptothecin, etoposide, or 50 ng doxorubicin) but not during apoptosis induced by Taxol or 10 mu g doxorubicin or autophagy induced by tamoxifen. The same alterations in CD and eEF1A1 levels were observed during replicative senescence and Ras oncogene-induced senescence. Transient cell cycle arrest did not alter levels of eEF1 or CD. Chemical inhibition of CD (pepstatin A) and small interfering RNA-mediated knockdown of CD and eEF1 revealed that these factors participate in cell proliferation. Finally, the senescence-associated alteration in CD and eEF1 levels observed in cell lines was also observed in IR-exposed xenografted tumors. These findings show that CD and eEF1 are promising markers for the detection of cellular senescence induced by a variety of treatments. [Cancer Res 2009;69(11):4638-47]