Schwarze Steven R, Fu Vivian X, Desotelle Joshua A, Kenowski Michelle L, Jarrard David F
Department of Surgery, University of Wisconsin and the University of Wisconsin Comprehensive Cancer Center, Madison, WI 53972, USA.
Neoplasia. 2005 Sep;7(9):816-23. doi: 10.1593/neo.05250.
Classic mechanisms of tumor response to chemotherapy include apoptosis and mitotic catastrophe. Recent studies have suggested that cellular senescence, a terminal proliferation arrest seen in vitro, may be invoked during the exposure of cancer cells to chemotherapeutic agents. To identify markers associated specifically with the cellular senescence phenotype, we utilized expression data from cDNA microarray experiments identifying transcripts whose expression levels increased as human prostate epithelial cells progressed to senescence. When screened against other growth-inhibitory conditions, including quiescence and apoptosis, many of these transcripts were also upregulated, indicating that similar pathways occur between apoptosis and senescence. A senescent-like phenotype was then induced in several prostate cancer cell lines using 5-aza-2'-deoxycytidine, doxorubicin, or Docetaxel. Treatment with these agents resulted in a significant increase in the induction of senescence-specific genes when compared to nonsenescent conditions. The performance of the panel was improved with fluorescence-activated cell sorting using PKH26 to isolate nonproliferating, viable, drug-treated populations, indicating that a heterogeneous response occurs with chemotherapy. We have defined an RNA-based gene panel that characterizes the senescent phenotype induced in cancer cells by drug treatment. These data also indicate that a panel of genes, rather than one marker, needs to be utilized to identify senescence.
肿瘤对化疗的经典反应机制包括细胞凋亡和有丝分裂灾难。最近的研究表明，细胞衰老，即在体外观察到的一种终末增殖停滞现象，可能在癌细胞暴露于化疗药物的过程中被引发。为了鉴定与细胞衰老表型特异性相关的标志物，我们利用了来自cDNA微阵列实验的表达数据，这些实验确定了随着人前列腺上皮细胞进入衰老状态其表达水平升高的转录本。当针对包括静止和凋亡在内的其他生长抑制条件进行筛选时，许多这些转录本也上调，这表明凋亡和衰老之间存在相似的途径。然后，使用5-氮杂-2'-脱氧胞苷、阿霉素或多西他赛在几种前列腺癌细胞系中诱导出衰老样表型。与非衰老条件相比，用这些药物处理导致衰老特异性基因的诱导显著增加。使用PKH26通过荧光激活细胞分选来分离未增殖的、存活的、药物处理的群体，提高了该检测方法的性能，这表明化疗会产生异质性反应。我们定义了一个基于RNA的基因检测板，其可表征药物处理在癌细胞中诱导的衰老表型。这些数据还表明，需要利用一组基因而不是一个标志物来鉴定衰老。
