Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted
Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted
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DOI：
10.1038/sj.bjc.6602962
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发表时间：
2006-02-27
影响因子：
8.8
通讯作者：
Coy, JF
中科院分区：
文献类型：
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作者：
Langbein, S;Zerilli, M;Coy, JF
即使在有氧的情况下，肿瘤也会将葡萄糖发酵为乳酸（有氧糖酵解；瓦尔堡效应）。磷酸戊糖途径 (PPP) 允许葡萄糖转化为核糖以进行核酸合成，并将葡萄糖降解为乳酸。 PPP 的非氧化部分由转酮醇酶反应控制。我们检测到人类恶性肿瘤中突变的转酮醇酶转录本 (TKTL1) 上调，而转酮醇酶 (TKT) 和转酮醇酶样 2 (TKTL2) 转录本并未上调。 TKTL1 蛋白的强表达与侵袭性结肠癌和尿路上皮肿瘤以及患者预后不良相关。 TKTL1 编码具有不寻常酶学性质的转酮醇酶，这可能是由保守残基的内部删除引起的。我们认为肿瘤中 TKTL1 的上调会导致不依赖于氧的葡萄糖使用量的增加和基于乳酸的基质降解。由于抑制转酮酶反应可抑制肿瘤生长和转移，因此 TKTL1 可能成为新型抗转酮酶癌症疗法的相关靶点。我们建议基于确定肿瘤代谢变化的个体化癌症治疗，这可能能够有针对性地抑制侵袭和转移。
Tumours ferment glucose to lactate even in the presence of oxygen ( aerobic glycolysis; Warburg effect). The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis and glucose degradation to lactate. The nonoxidative part of the PPP is controlled by transketolase enzyme reactions. We have detected upregulation of a mutated transketolase transcript (TKTL1) in human malignancies, whereas transketolase (TKT) and transketolase-like-2 (TKTL2) transcripts were not upregulated. Strong TKTL1 protein expression was correlated to invasive colon and urothelial tumours and to poor patients outcome. TKTL1 encodes a transketolase with unusual enzymatic properties, which are likely to be caused by the internal deletion of conserved residues. We propose that TKTL1 upregulation in tumours leads to enhanced, oxygen-independent glucose usage and a lactate-based matrix degradation. As inhibition of transketolase enzyme reactions suppresses tumour growth and metastasis, TKTL1 could be the relevant target for novel anti-transketolase cancer therapies. We suggest an individualised cancer therapy based on the determination of metabolic changes in tumours that might enable the targeted inhibition of invasion and metastasis.