Transketolase like 1 (TKTL1) expression alterations in prostate cancer tumorigenesis

Costa, Inês Anselmo da; Hennenlotter, Jörg; Stühler, Viktoria; Kühs, Ursula; Scharpf, Marcus; Todenhöfer, Tilman; Stenzl, Arnulf; Bedke, Jens

doi:10.1016/j.urolonc.2018.06.010

Cited by 19 publications

(11 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In rapidly dividing cancer cells, the PPP is tailored to generate pentose phosphates from G6P in the oxidative branch and fructose-6-phosphate (F6P) and glyceraldehyde-3-phosphate (G3P) in the nonoxidative branch. Cancer cells increase their expression of TKT and TALDO to accelerate the nonoxidative branch of the PPP [ 49 ], with elevated levels of TKT reported in lung, breast, and prostate cancer cells [ 52 , 61 , 62 , 63 ], and elevated levels of TALDO reported in gastric adenocarcinoma [ 64 ]. Both TKT and TALDO expression is increased in response to Nuclear Factor, Erythroid 2-Like 2 (NRF2) activation, an important sensor of oxidative stress [ 65 , 66 ].…”

Section: Pentose Phosphate Pathwaymentioning

confidence: 99%

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Schiliro

Firestein

2021

Cells

321

152

View full text Add to dashboard Cite

Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.

show abstract

Section: Pentose Phosphate Pathwaymentioning

confidence: 99%

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Schiliro

Firestein

2021

Cells

321

152

View full text Add to dashboard Cite

show abstract

“…Frigo and colleagues recently demonstrated that G6PD, the rate-limiting enzyme of this pathway, is also transcriptionally and post-transcriptionally regulated by AR signalling ( Tsouko et al, 2014 ). Moreover, an enzyme that regulates the non-oxidative phase of the PPP, transketolase-like protein 1 (TKTL1), increases in expression during PCa progression, being highest in metastatic tumours ( da Costa et al, 2018 ). Such multi-level control of a single pathway emphasises the relevance of increased PPP flux in PCa.…”

Section: Discussionmentioning

confidence: 99%

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

Gillis

Hinneh

Ryan

et al. 2021

eLife

View full text Add to dashboard Cite

Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity, as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively-collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by ACC1 and mTOR; and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

show abstract

“…Most of the studies included in this review were based on the analysis of blood or urine samples, probably due to their easy accessibility and non-invasiveness. NMR and MS are the two most commonly used analytical platforms in these studies, though other analytical techniques have also been applied to the identification of PCa-related metabolic changes [58,93,94,95]. Although a significant number of studies focused on the identification of biomarkers for PCa diagnosis, some of them also explored the potential of metabolic biomarkers for patient prognosis and PCa risk evaluation.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Metabolomics Contributions to the Discovery of Prostate Cancer Biomarkers

et al. 2019

View full text Add to dashboard Cite

Prostate cancer (PCa) is one of the most frequently diagnosed cancers and a leading cause of death among men worldwide. Despite extensive efforts in biomarker discovery during the last years, currently used clinical biomarkers are still lacking enough specificity and sensitivity for PCa early detection, patient prognosis, and monitoring. Therefore, more precise biomarkers are required to improve the clinical management of PCa patients. In this context, metabolomics has shown to be a promising and powerful tool to identify novel PCa biomarkers in biofluids. Thus, changes in polyamines, tricarboxylic acid (TCA) cycle, amino acids, and fatty acids metabolism have been reported in different studies analyzing PCa patients’ biofluids. The review provides an up-to-date summary of the main metabolic alterations that have been described in biofluid-based studies of PCa patients, as well as a discussion regarding their potential to improve clinical PCa diagnosis and prognosis. Furthermore, a summary of the most significant findings reported in these studies and the connections and interactions between the different metabolic changes described has also been included, aiming to better describe the specific metabolic signature associated to PCa.

show abstract

Transketolase like 1 (TKTL1) expression alterations in prostate cancer tumorigenesis

Cited by 19 publications

References 30 publications

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

Metabolomics Contributions to the Discovery of Prostate Cancer Biomarkers

Contact Info

Product

Resources

About