Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes.
Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes.
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DOI：
10.1186/1471-2407-14-223
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发表时间：
2014-03-25
期刊：
影响因子：
3.8
通讯作者：
Hu S
中科院分区：
文献类型：
--
作者：
Zhang M;Chai YD;Brumbaugh J;Liu X;Rabii R;Feng S;Misuno K;Messadi D;Hu S
癌细胞可能经历代谢适应，以支持其生长和耐药特性。本研究的目的是测试口腔癌细胞是否可以通过小干扰RNA （small interfering RNA, siRNA）敲低其重要代谢酶的表达来克服代谢缺陷。用siRNA转染UM1和UM2口腔癌细胞转酮醇酶（TKT）或siRNA转染腺苷酸激酶（AK2），用Western blotting证实其下调。我们比较了TKT或AK2基因敲低的癌细胞和转染对照siRNA的癌细胞对葡萄糖和谷氨酰胺的摄取以及乳酸的产生。采用学生t检验进行统计学分析。尽管TKT的siRNA敲低导致戊糖磷酸途径的缺陷，但存活的UM1或UM2细胞利用了更多的葡萄糖和谷氨酰胺，分泌的乳酸量明显高于对照siRNA转移的细胞。我们还证明，AK2的siRNA敲低抑制了UM1和UM2细胞的增殖，但同样导致AK2 siRNA沉默后存活的UM1或UM2细胞对葡萄糖/谷氨酰胺的摄取增加和乳酸的产生。我们的研究结果表明，由siRNA沉默代谢酶TKT或AK2引入的代谢缺陷可能通过其他反馈代谢机制得到补偿，这表明癌细胞可能通过次级代谢网络适应来克服单一缺陷途径。口腔癌细胞代谢的高度健壮性意味着可能需要针对多种代谢途径的系统医学方法来实现癌症治疗的持续改进。
Cancer cells may undergo metabolic adaptations that support their growth as well as drug resistance properties. The purpose of this study is to test if oral cancer cells can overcome the metabolic defects introduced by using small interfering RNA (siRNA) to knock down their expression of important metabolic enzymes. UM1 and UM2 oral cancer cells were transfected with siRNA to transketolase (TKT) or siRNA to adenylate kinase (AK2), and Western blotting was used to confirm the knockdown. Cellular uptake of glucose and glutamine and production of lactate were compared between the cancer cells with either TKT or AK2 knockdown and those transfected with control siRNA. Statistical analysis was performed with student T-test. Despite the defect in the pentose phosphate pathway caused by siRNA knockdown of TKT, the survived UM1 or UM2 cells utilized more glucose and glutamine and secreted a significantly higher amount of lactate than the cells transferred with control siRNA. We also demonstrated that siRNA knockdown of AK2 constrained the proliferation of UM1 and UM2 cells but similarly led to an increased uptake of glucose/glutamine and production of lactate by the UM1 or UM2 cells survived from siRNA silencing of AK2. Our results indicate that the metabolic defects introduced by siRNA silencing of metabolic enzymes TKT or AK2 may be compensated by alternative feedback metabolic mechanisms, suggesting that cancer cells may overcome single defective pathways through secondary metabolic network adaptations. The highly robust nature of oral cancer cell metabolism implies that a systematic medical approach targeting multiple metabolic pathways may be needed to accomplish the continued improvement of cancer treatment.
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影响因子：
3.5
作者：
Köhler, C;Gahm, A;Zhivotovsky, B
通讯作者：
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DOI：
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