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

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 lactatebased 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.

Research and Therapeutic Innovation: Tissue Resonance InterferoMeter Probe in Early Detection-Screening for Rectal Cancer

“…Among colon and uroepithelial cancer patients, the expression level of transketolase-like gene 1 (one of the transketolase genes) was strongly related to the patients' survival rate. Autopsy results confirmed the correlation between increased expression of transketolase-like gene 1 and a higher mortality rate (Langbein et al, 2006). Several factors contribute to cellular oxidative stress, which occurs when the balance between oxidants and antioxidants is disrupted, resulting in an overall increase in reactive oxygen species (ROS).…”

Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

“…44 TKTL1 activity has been shown to supply ~85% of the C5-ribose sugars for nucleic acid synthesis, be overexpressed in a range of cancers including breast, and be essential for tumor cell proliferation. [45][46][47][48][49][50] Our results not only demonstrated an increase in SLC19A3 transporter expression but an increase in overall thiamine transport which could potentially be supporting the glycolytic phenotype of hypoxic cancer cells (Fig. 3).…”

Transketolase protein TKTL1 overexpression: A potential biomarker and therapeutic target in breast cancer

“…The relative contributions of TKT, TKTL1 and TKTL2 to tumorspecific transketolase metabolism have been investigated in a recent study which found a specific TKTL1 overexpression in urothelial and colon carcimomas at the mRNA and protein level, whereas TKT-and TKTL2-expression are not upregulated. Overexpression of TKTL1 protein predicted poor patient survival (10).…”