The role of spermidine/spermine N1-acetyltransferase in determining response to chemotherapeutic agents in colorectal cancer cells
The role of spermidine/spermine N1-acetyltransferase in determining response to chemotherapeutic agents in colorectal cancer cells
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DOI：
10.1158/1535-7163.mct-06-0303
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发表时间：
2007-01-01
影响因子：
5.7
通讯作者：
Johnston, Patrick G.
中科院分区：
文献类型：
--
作者：
Allen, Wendy L.;McLean, Estelle G.;Johnston, Patrick G.
多胺已被证明在几种实体瘤（包括结直肠癌）的生长和存活中发挥作用。我们确定了多胺分解代谢酶亚精胺/精胺N-1-乙酰转移酶（SSAT）作为最高度诱导基因之一，在两个DNA微阵列筛选，以确定新的决定因素，在结直肠癌化疗药物的反应。在亲本和耐药HCT 116细胞系中，SSAT被证明对5-氟尿嘧啶（5-FU）或奥沙利铂有诱导反应。研究还表明，在一组6种结直肠癌细胞系中，SSAT mRNA响应于5-FU或奥沙利铂而上调。多胺类似物N-1，N-11-二乙基去甲精胺（DENSpm）耗尽多胺库，并有效地诱导SSAT。我们评估了DENSpm与化疗药物联合在HCT 116 p53（+/+）细胞和HCT 116耐药子细胞系中的作用。Western blot分析显示，当DENSpm与奥沙利铂或5-FU联合使用时，HCT 116 p53（+/+）细胞中SSAT蛋白表达显著增强。使用细胞活力测定和流式细胞术，在用DENSpm和每种化疗剂共处理HCT 116 p53（+/+）细胞后观察到细胞死亡的协同诱导。值得注意的是，这种联合疗法增加了对这些化疗剂中的每一种产生抗性的细胞的化学敏感性。小干扰RNA介导的SSAT下调导致DENSpm和这些药物之间的协同作用丧失。这些结果表明，SSAT在细胞毒性药物和DENSpm联合治疗后调节细胞死亡中起重要作用。此外，DENSpm使敏感细胞和抗性细胞对化疗剂敏感。总而言之，这些结果表明SSAT可能是结直肠癌治疗干预的重要靶点。
Polyamines have been shown to play a role in the growth and survival of several solid tumors, including colorectal cancer. We identified the polyamine catabolic enzyme spermidine/spermine N-1-acetyltransferase (SSAT) as being one of the most highly inducible genes in two DNA microarray screens to identify novel determinants of response to chemotherapeutic agents in colorectal cancer. SSAT was shown to be inducible in response to 5-fluorouracil (5-FU) or oxaliplatin in parental and drug-resistant HCT116 cell lines. It was also shown that SSAT mRNA was up-regulated in response to 5-FU or oxaliplatin in a panel of six colorectal cancer cell lines. The polyamine analogue N-1,N-11-diethylnorspermine (DENSpm) depletes polyamine pools and potently induces SSAT. We evaluated the effect of combining DENSpm with chemotherapeutic agents in HCT116 p53(+/+) cells and in HCT116 drug-resistant daughter cell lines. Western blot analyses showed that SSAT protein expression was dramatically enhanced when DENSpm was combined with oxaliplatin or 5-FU in HCT116 p53(+/+) cells. Using cell viability assays and flow cytometry, synergistic induction of cell death was observed following cotreatment of HCT116 p53(+/+) cells with DENSpm and each chemotherapeutic agent. Of note, this combined therapy increased the chemosensitivity of cells rendered resistant to each of these chemotherapeutic agents. Small interfering RNA-mediated down-regulation of SSAT resulted in loss of synergy between DENSpm and these agents. These results show that SSAT plays an important role in regulating cell death following combined cytotoxic drug and DENSpm treatment. Furthermore, DENSpm sensitizes both sensitive and resistant cells to chemotherapeutic agents. Taken together, these results suggest that SSAT may be an important target for therapeutic intervention in colorectal cancer.