1. ¹Department of Urology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
2. ²Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè, 5, 90127 Palermo, Italy
3. ³Institute of Pathology, University Hospital Freiburg, Albertstr. 19, 79002 Freiburg, Germany
4. ⁴Department of Surgery, University Hospital Mannheim, Ruprecht-Karls-University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
5. ⁵TAVARTIS GmbH, Kroetengasse 10, 64853 Otzberg, Germany
6. ⁶Institute of Pathology, University of Palermo, Via del Vespro, 129, 90127 Palermo, Italy
7. ⁷Department of Biostatistics, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
8. ⁸Department of Pathology, University Hospital Mannheim, Ruprecht-Karls-University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
9. ⁹R-Biopharm AG, Landwehrstrasse 54, 64293 Darmstadt, Germany

Correspondence: Dr JF Coy, E-mail: j.coy@r-biopharm.de or coy@tavartis.com

¹⁰These authors equally contributed to this work.

¹¹Present address: Department of Urology, Academic Medical Center, Postbus 22660, Amsterdam 1100 DD, The Netherlands

Received 12 August 2005; Revised 6 December 2005; Accepted 14 December 2005; Published online 7 February 2006.

Abstract

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.