Low cytosine triphosphate synthase 2 expression renders resistance to 5-fluorouracil in colorectal cancer
Low cytosine triphosphate synthase 2 expression renders resistance to 5-fluorouracil in colorectal cancer
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DOI：
10.4161/cbt.11.6.14670
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发表时间：
2011-03-15
影响因子：
3.6
通讯作者：
Soong, Richie
中科院分区：
文献类型：
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作者：
Tan, Wen Lee;Bhattacharya, Bhaskar;Soong, Richie
了解5-氟尿嘧啶（5FU）耐药的决定因素对优化给药、引入新的药物和治疗策略具有重要价值。本研究采用实时荧光定量PCR低密度阵列技术，在14例具有5FU耐药性的患者源性结直肠癌异种移植物中检测了92个参与5FU转运、代谢、辅助因子（叶酸）代谢和下游效应的基因的表达。通过siRNA和尿苷调节、免疫印迹、细胞凋亡和细胞周期分析检测候选基因的功能。通过免疫组化对125例接受和未接受5FU治疗的III期结直肠癌患者的肿瘤进行预测意义检验。在5FU敏感和耐药异种移植物肿瘤间8个显著差异表达的基因中，CTPS2是差异表达概率最高的基因（p = 0.008）。通过siRNA降低CTPS2的表达增加了结直肠癌细胞系DLD1和LS174T对5FU及其类似物FUDR的抗性。CTPS2 siRNA显著降低5FU处理后细胞s期积累和凋亡。尿嘧啶是CTPS2底物尿嘧啶三磷酸的前体，细胞暴露于尿嘧啶也增加了5FU耐药性。低CTPS2患者没有从5FU治疗中获得生存获益（p = 0.072），而高表达患者获得了生存获益（p = 0.003）。CTPS2低表达可能是5FU耐药的合理决定因素。
Understanding the determinants of resistance of 5-fluorouracil (5FU) is of significant value to optimizing administration of the drug, and introducing novel agents and treatment strategies. Here, the expression of 92 genes involved in 5FU transport, metabolism, co-factor (folate) metabolism and downstream effects was measured by real-time PCR low density arrays in 14 patient-derived colorectal cancer xenografts characterized for 5FU resistance. Candidate gene function was tested by siRNA and uridine modulation, and immunoblotting, apoptosis and cell cycle analysis. Predictive significance was tested by immunohistochemistry of tumors from 125 stage III colorectal cancer patients treated with and without 5FU. Of 8 genes significantly differentially expressed between 5FU sensitive and resistant xenograft tumors, CTPS2 was the gene with the highest probability of differential expression (p = 0.008). Reduction of CTPS2 expression by siRNA increased the resistance of colorectal cancer cell lines DLD1 and LS174T to 5FU and its analog, FUDR. CTPS2 siRNA significantly reduced cell S-phase accumulation and apoptosis following 5FU treatment. Exposure of cells to uridine, a precursor to the CTPS2 substrate uridine triphosphate, also increased 5FU resistance. Patients with low CTPS2 did not gain a survival benefit from 5FU treatment (p = 0.072), while those with high expression did (p = 0.003). Low CTPS2 expression may be a rationally-based determinant of 5FU resistance.