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Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted

机译:转酮醇酶TKTL1的表达预测结肠癌和尿路上皮癌患者的生存:重新解释了Warburg效应

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摘要

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.
机译:甚至在有氧的情况下,肿瘤也会将葡萄糖发酵为乳酸(有氧糖酵解;沃伯格效应)。磷酸戊糖途径(PPP)允许葡萄糖转化为核糖用于核酸合成,而葡萄糖降解为乳酸盐。 PPP的非氧化部分受转酮酶反应控制。我们已经检测到人类恶性肿瘤中的突变的转酮醇酶转录物(TKTL1)上调,而转酮醇酶(TKT)和转酮醇酶样2(TKTL2)转录物却未上调。 TKTL1蛋白的强表达与浸润性结肠癌和尿路上皮肿瘤以及不良的患者预后相关。 TKTL1编码具有非常规酶学性质的转酮醇酶,这很可能是由保守残基的内部缺失引起的。我们建议,肿瘤中的TKTL1上调会导致增强的,与氧无关的葡萄糖用量和基于乳酸的基质降解。由于抑制转酮酶酶反应可抑制肿瘤的生长和转移,因此TKTL1可能是新型抗转酮酶疗法的相关靶标。我们建议根据肿瘤代谢变化的确定情况进行个体化癌症治疗,从而可能有针对性地抑制侵袭和转移。

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