Metastasis is promoted by a bioenergetic switch: New targets for progressive renal cell cancer
Metastasis is promoted by a bioenergetic switch: New targets for progressive renal cell cancer
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DOI：
10.1002/ijc.23403
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发表时间：
2008-06-01
影响因子：
6.4
通讯作者：
Coy, Johannes F.
中科院分区：
文献类型：
--
作者：
Langbein, Sigrun;Frederiks, Wilma M.;Coy, Johannes F.
肾细胞癌(RCC)的靶向治疗已显示出临床益处，但对长期疾病特异性生存的影响有限。需要治疗耐药或复发的肿瘤的新机会。增加厌氧葡萄糖发酵为乳酸(有氧糖酵解)，导致氧和线粒体不依赖的ATP生成是侵袭性癌症生长的标志。这种代谢变化通过磷酸戊糖途径(PPP)循环导致乳酸产量增加，并在肿瘤免疫逃逸、进展和对免疫、放射和化疗的抵抗中发挥重要作用。本研究探讨氧化和非氧化分支或PPP在肾癌中的活性和影响，以评估新的治疗方案。氧化分支的活性由冰糖-6-磷酸脱氢酶(G6PD)活性确定，非氧化分支的活性由总转酮醇酶活性和转酮醇酶样蛋白1(TKTL1)的特异性表达来确定。肿瘤组织中转酮醇酶和G6PD活性明显升高。转酮醇酶活性在转移性肿瘤中升高更明显，而TKTL1蛋白在进展期肿瘤中明显过度表达(p=0.03)。致命性肿瘤，如分级和分期等替代参数未能预测进展，显示出强烈的TKTL1蛋白表达。RCC被发现通过PPP激活了氧化和非氧化葡萄糖代谢，在进展的肿瘤中显示出生物能量向非氧化性葡萄糖发酵的转变。癌细胞与不同调节的能量供应共存为癌症发生和新的抗癌靶点提供了新的见解。(C)2008年Wiley-Liss，Inc.
Targeted therapies have demonstrated clinical benefit with limited impact on long-term disease specific survival in the treatment of renal cell cancer (RCC). New opportunities for the treatment of tumors that are resistant or have relapsed, are needed. Increased anaerobic glucose fermentation to lactate (aerobic glycolysis), leading to oxygen- and mitochondria-independent ATP generation is a hallmark of aggressive cancer growth. This metabolic shift results in increased lactate production via cycling through the pentose phosphate pathway (PPP), and plays an important role in tumor immune escape, progression and resistance to immune-, radiation- and chemo-therapy. This study explored the activity and impact of the oxidative and nonoxidative branches or the PPP on RCC to evaluate new therapeutic options. Activity was determined in the oxidative branch by glacose-6-phosphate-dehydrogenase (G6PD) activity, and in the nonoxidative branch by the total transketolase activity and the specific expression of the transketolase-like-1 (TKTL1) protein. Transketolase and G6PD activity were intensely elevated in tumor tissues. Transketolase, but not G6PD activity, was more elevated in metastasizing tumors and TKTL1 protein was significantly overexpressed in progressing tumors (p = 0.03). Lethal tumors, where surrogate parameters such as grading and staging had failed to predict progression, showed intensive TKTL1 protein expression. RCC was found to have activated oxidative and nonoxidative glucose metabolism through the PPP, displaying a bioenergetic shift toward nonoxiclative glucose fermentation in progressing tumors. The coexistence of cancer cells with differentially regulated energy supplies provides new insights in carcinogenesis and novel anticancer targets. (C) 2008 Wiley-Liss, Inc.