Is transketolase like 1 a target for the treatment of differentiated thyroid carcinoma? A study on thyroid cancer cell lines

Frőhlich, Eleonore; Fink, I.R.; Wahl, Richard L.

doi:10.1007/s10637-008-9174-8

Cited by 15 publications

(12 citation statements)

References 28 publications

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“…This is in accordance with a significant overexpression of TKTL1 in several different tumors like nasopharyngeal [16] , pulmonary [17] , thyroid papillary [18,19] , gastric [20] , ovarian [21,22] , cervical [23] and metastasizing renal cell carcinoma [11] . In general, increased TKTL1 expression correlates with poor patient outcome and tumor progression [20,[23][24][25] .…”

Section: Introductionsupporting

confidence: 82%

Hypoxia Induces the Expression of Transketolase-Like 1 in Human Colorectal Cancer

Bentz¹,

Cee²,

Endlicher

et al. 2013

Digestion

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Background and Aims: Transketolase-like (TKTL) 1 is one of the key enzymes for anaerobic sugar degradation even in the presence of oxygen (aerobic glycolysis). Transketolase-dependent reactions supply malignant tumors with ribose and NADPH. Therefore, TKTL1 activity could be crucial for tumor proliferation and survival. The aim of the study was to evaluate the expression of TKTL1 in colorectal cancer (CRC) and its regulation under hypoxic conditions. Methods: We studied TKTL1 mRNA and protein expression in CRC cell lines and human CRC biopsies by quantitative real-time PCR, Western blotting and immunohistochemistry. Regulation of TKTL1 under oxygen depletion was analyzed by cultivating cells either in a three-dimensional spheroid model or in a hypoxia incubator chamber. Results: TKTL1 mRNA was heterogeneously expressed in monolayers of cells with high levels in HT-29 and SW480. TKTL1 protein was also clearly detectable in HT-29 and SW480. Hypoxia-inducible factor (HIF)-1 protein expression correlated with TKTL1 protein expression in SW480 spheroids over time. On the one hand, induction of hypoxia in T84 spheroids did not induce TKTL1; on the other hand, hypoxia by incubation at 1% O2 in a hypoxia incubator chamber clearly showed an upregulation of TKTL1. In 50% of CRC patients, TKTL1 protein expression was upregulated in tumor compared to non-tumor tissue. The immunohistochemical staining of TKTL1 in CRC patient samples resulted in 14 positive and 30 negative samples. Conclusions: TKTL1 expression correlated with HIF-1 protein expression and was induced upon hypoxic conditions which could facilitate energy supply to tumors under these circumstances. © 2013 S. Karger AG, Basel.

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Section: Introductionsupporting

confidence: 82%

Hypoxia Induces the Expression of Transketolase-Like 1 in Human Colorectal Cancer

Bentz¹,

Cee²,

Endlicher

et al. 2013

Digestion

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“…According to the results of several clinical studies, overexpression of TKTL-1 is associated with a poor prognosis (2)(3)(4)(5). Experimental data have been published (1,(6)(7)(8) which apparently confirm the pathophysiological basis of TKTL-1-associated aggressiveness observed in clinical studies. Coy et al (1) hypothesized that energy production of malignant cells is crucially dependent upon TKTL-1-mediated degradation of glucose to lactate.…”

Section: Introductionmentioning

confidence: 57%

Glucose metabolism of malignant cells is not regulated by transketolase-like (TKTL)-1

Mayer

Wallbrunn²,

Vaupel³

2010

Int J Oncol

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Abstract. An isoenzyme of transketolase, transketolase-like (TKTL)-1, has been hypothesized to play a pivotal role in the pathophysiology of malignant tumors. Available data are based on the detection of the putative TKTL-1 protein with one particular mouse monoclonal anti-TKTL-1 antibody, clone JFC12T10. In this study it was demonstrated that a) JFC12T10 detects multiple unspecific bands in Western blots, b) a 75-kDa band hitherto referred to as TKTL-1 corresponds to a nuclear protein and c) immunohistochemical detection of TKTL-1 in benign leiomyomas yields an expression pattern identical to that found in a variety of malignant tumors. In RT-PCR assays, using three different primer pairs for transketolase, TKTL-1 and yet another isogene of transketolase, TKTL-2, a relevant expression of TKTL-1 was not detectable in any of the 6 malignant tumor cell lines investigated (MCF-7, A549, HeLa, HT1080, M21 and TF-1). Expression levels of TKTL-1 were rather similar to those found for TKTL-2, although the latter has never been implicated in malignant disease. On the basis of these data, nutritional recommendations based on a hypothetically TKTL-1 controlled metabolism of tumor cells must be regarded as lacking scientific evidence.

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“…Furthermore, recent structural and mutagenesis studies questioned the catalytic competence of the tumor‐specific isoform of transketolase, transketolase‐like protein 1 . Catalytic incompetence of transketolase‐like protein 1 may explain the results of an independent in vivo study which showed that overexpression of transketolase‐like protein 1 in cancer cells was not strongly correlated with their proliferation rate, glucose transporter‐1 expression and response to oxythiamin . In another study, the thiamin antagonist N3′–pyridyl thiamin (Fig.…”

Section: Thdp‐dependent Enzymes In the Directed Metabolic Regulationmentioning

confidence: 99%

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models

Bunik

Tylicki

Lukashev

2013

FEBS J

102

128

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Bringing a knowledge of enzymology into research in vivo and in situ is of great importance in understanding systems biology and metabolic regulation. The central metabolic significance of thiamin (vitamin B 1 ) and its diphosphorylated derivative (thiamin diphosphate; ThDP), and the fundamental differences in the ThDP-dependent enzymes of metabolic networks in mammals versus plants, fungi and bacteria, or in health versus disease, suggest that these enzymes are promising targets for biotechnological and medical applications. Here, the in vivo action of known regulators of ThDP-dependent enzymes, such as synthetic structural analogs of the enzyme substrates and thiamin, is analyzed in light of the enzymological data accumulated during half a century of research. Mimicking the enzyme-specific catalytic intermediates, the phosphonate analogs of 2-oxo acids selectively inhibit particular ThDP-dependent enzymes. Because of their selectivity, use of these compounds in cellular and animal models of ThDP-dependent enzyme malfunctions improves the validity of the model and its predictive power when compared with the nonselective and enzymatically less characterized oxythiamin and pyrithiamin. In vitro studies of the interaction of thiamin analogs and their biological derivatives with potential in vivo targets are necessary to identify and attenuate the analog selectivity. For both the substrate and thiamin synthetic analogs, in vitro reactivities with potential targets are highly relevant in vivo. However, effective concentrations in vivo are often higher than in vitro studies would suggest. The significance of specific inihibition of the ThDP-dependent enzymes for the development of herbicides, antibiotics, anticancer and neuroprotective strategies is discussed.

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Is transketolase like 1 a target for the treatment of differentiated thyroid carcinoma? A study on thyroid cancer cell lines

Cited by 15 publications

References 28 publications

Hypoxia Induces the Expression of Transketolase-Like 1 in Human Colorectal Cancer

Hypoxia Induces the Expression of Transketolase-Like 1 in Human Colorectal Cancer

Glucose metabolism of malignant cells is not regulated by transketolase-like (TKTL)-1

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models

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