Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells
Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells
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DOI：
10.1002/ijc.24078
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发表时间：
2009-03-15
影响因子：
6.4
通讯作者：
Loechelt, Martin
中科院分区：
文献类型：
--
作者：
Xu, Xiaojun;zur Hausen, Axel;Loechelt, Martin
癌细胞表现出很高的有氧糖酵解，这一现象被称为沃堡效应。乳酸和丙酮酸是糖酵解的最终产物，即使在氧气存在的情况下，癌细胞也会过度生产。磷酸戊糖途径(PPP)允许葡萄糖转化为核糖以合成核酸，葡萄糖降解为乳酸，以及氧化还原等价物的再生。PPP的非氧化部分由转酮醇酶(TKT)控制。作为一种TKT亚型，转酮醇类蛋白1(TKTL1)在不同的人类癌症中特异上调，其过度表达预测贫困患者的生存。这一发现暗示，TKTL1表达的增加可能激活PPP，从而促进癌细胞的生长和存活。为了分析TKTL1在恶性进展中的功能作用，我们利用RNAi技术在人结肠癌细胞中抑制了TKTL1。TKTL1抑制导致细胞生长、葡萄糖消耗和乳酸产生明显减慢。在TKTL1基因敲除细胞中，细胞内活性氧水平没有明显增加，但对氧化应激诱导的细胞凋亡的敏感性明显增强。这些数据为TKTL1dys调控在肿瘤细胞中的重要性提供了新的线索，并表明TKTL1的过表达不仅可能被认为是一个新的肿瘤标志物，而且可能是一个良好的抗癌治疗靶点。(C)2008年Wiley-Liss，Inc.
Cancer cells display high rates of aerobic glycolysis, a phenomenon known as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are overproduced by cancer cells even in the presence of oxygen. The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis, glucose degradation to lactate, and regeneration of redox equivalents. The nonoxidative part of the PPP is controlled by transketolase (TKT) enzymes. One TKT isoform, the transketolase-like protein 1 (TKTL1) is specifically upregulated in different human cancers and its overexpression predicts a poor patient's survival. This finding implicates that an increased TKTL1 expression may activate the PPP leading to enhanced cancer cell growth and survival. To analyze the functional role of TKTL1 in malignant progression, we inhibited TKTL1 by RNAi technologies in human HCT116 colon carcinoma cells. TKTL1 suppression resulted in a significantly slowed cell growth, glucose consumption and lactate production. In TKTL1 knockdown-cells, the intracellular reactive oxygen species levels were not significantly increased, whereas the sensitivity towards oxidative stress-induced apoptosis was clearly enhanced. These data provide new clues on the importance of TKTL1 dys-regulation in tumor cells and indicate that TKTL1 overexpression may be considered not only as a new tumor marker but also as a good target for anticancer therapy. (c) 2008 Wiley-Liss, Inc.