The role of transketolase in human cancer progression and therapy

Hao, Shiming; Meng, Qingfei; Sun, Huihui; Li, Yunkuo; Li, Yao; Gu, Liting; Liu, Bin; Zhang, Yanghe; Zhou, Honglan; Xu, Zhixiang; Wang, Yishu

doi:10.1016/j.biopha.2022.113607

Cited by 23 publications

(15 citation statements)

References 142 publications

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“…High expression of TKTL1 has been correlated with poor prognosis in several tumors. 45 SLC16A1 was shown to be expressed at higher levels in GBM in comparison with LGG. 46,47 However, the influence of SLC16A1 expression level on the prognosis of GBM remains inconclusive.…”

Section: Discussionmentioning

confidence: 94%

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Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

Zhang,

Wang,

Zheng

et al. 2023

Cancer Medicine

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BackgroundGlioblastoma (GBM), the most common primary malignant brain tumor, has a poor prognosis, with a median survival of only 14.6 months. The Warburg effect is an abnormal energy metabolism, which is the main cause of the acidic tumor microenvironment. This study explored the role of the Warburg effect in the prognosis and immune microenvironment of GBM.MethodsA prognostic risk score model of Warburg effect‐related genes (Warburg effect signature) was constructed using GBM cohort data from The Cancer Genome Atlas. Cox analysis was performed to identify independent prognostic factors. Next, the nomogram was built to predict the prognosis for GBM patients. Finally, the drug sensitivity analysis was utilized to find the drugs that specifically target Warburg effect‐related genes.ResultsAge, radiotherapy, chemotherapy, and WRGs score were confirmed as independent prognostic factors for GBM by Cox analyses. The C‐index (0.633 for the training set and 0.696 for the validation set) and area under curve (>0.7) indicated that the nomogram exhibited excellent performance. The calibration curve also indicates excellent consistency of the nomogram between predictions and actual observations. In addition, immune microenvironment analysis revealed that patients with high WRGs scores had high immunosuppressive scores, a high abundance of immunosuppressive cells, and a low response to immunotherapy. The Cell Counting Kit‐8 assays showed that the drugs targeting Warburg effect‐related genes could inhibit the GBM cells growth in vitro.ConclusionOur research showed that the Warburg effect is connected with the prognosis and immune microenvironment of GBM. Therefore, targeting Warburg effect‐related genes may provide novel therapeutic options.

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Section: Discussionmentioning

confidence: 94%

“…The high level of GPR68 expression possibly indicates the short survival rate of tumors. High expression of TKTL1 has been correlated with poor prognosis in several tumors 45 . SLC16A1 was shown to be expressed at higher levels in GBM in comparison with LGG 46,47 .…”

Section: Discussionmentioning

confidence: 95%

Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

Zhang,

Wang,

Zheng

et al. 2023

Cancer Medicine

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“…Cells are surrounded by a complex microenvironment in living bodies, and intercellular signal transduction occurs to transfer information by physical and chemical approaches, thus regulating cell behaviors, such as cell proliferation, apoptosis, differentiation, and stimulus response. , The investigation of intercellular signal transduction is important to many biological fields, including cancer research, immunology, and medicinal development. − …”

Section: Introductionmentioning

confidence: 99%

In Situ Investigation of Intercellular Signal Transduction Based on Detection of Extracellular pH and ROS by Scanning Electrochemical Microscopy

Jing

Lü

et al. 2023

Anal. Chem.

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Intercellular signal transduction plays an important role in the regulation of biological activities. Herein, a Transwell chamber-based two-layer device combined with scanning electrochemical microscopy (SECM) technology has been proposed for in situ investigation of intercellular signal transduction. The cells in the device were cultured on two layers: the lower layer was for signaling cells, and the upper layer was for signal-receiving cells. The extracellular pH (pHe) and ROS (reactive oxygen species, ROSe) were in situ monitored by SECM potentiometric mode and SECM-MPSW (multipotential step waveform), respectively. When the signaling cells, including MCF-7, HeLa, and HFF cells, were electrically stimulated, the ROS release of the signal-receiving cells was promoted. By detecting the pH at the cell surface, it was found that more H + generated by the signaling cells and two cell layers at a shorter distance could both cause the signal-receiving cells to release more ROS, revealing that H + is one of the signaling molecules of intercellular communication. This SECM-based in situ monitoring strategy provides an effective way to investigate intercellular signal transduction and explore the corresponding mechanism.

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“…Thus, TKT is a potential therapeutic target for cancer therapy. 10 To date, few inhibitors have been shown to inhibit TKT with low efficacy or unpredictable side effects in clinical trials. 11 Therefore, highly potent and selective TKT inhibitors are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

“…Upregulated TKT family genes have been identified in multiple types of cancer—including hepatocellular carcinoma (HCC), breast cancer, ovarian cancer, oesophageal cancer, lung cancer, and head‐and‐neck cancer, and is indicative of a poor prognosis. Thus, TKT is a potential therapeutic target for cancer therapy 10 . To date, few inhibitors have been shown to inhibit TKT with low efficacy or unpredictable side effects in clinical trials 11 .…”

Section: Introductionmentioning

confidence: 99%

Novel transketolase inhibitor oroxylin A suppresses the non‐oxidative pentose phosphate pathway and hepatocellular carcinoma tumour growth in mice and patient‐derived organoids

Jia

Liu

Zhu

et al. 2022

Clinical & Translational Med

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Background Transketolase (TKT), a key rate‐limiting enzyme in the non‐oxidative branch of the pentose phosphate pathway (PPP), provides more than 85% of the ribose required for de novo nucleotide biosynthesis and promotes the development of hepatocellular carcinoma (HCC). Pharmacologic inhibition of TKT could impede HCC development and enhance treatment efficacy. However, no safe and effective TKT inhibitor has been approved. Methods An online two‐dimensional TKT protein immobilised biochromatographic system was established for high‐throughput screening of TKT ligands. Oroxylin A was found to specifically bind TKT. Drug affinity responsive target stability, cellular thermal shift assay, surface plasmon resonance, molecular docking, competitive displacement assay, and site mutation were performed to identify the binding of oroxylin A with TKT. Antitumour effects of oroxylin A were evaluated in vitro, in human xenograft mice, diethylnitrosamine (DEN)‐induced HCC mice, and patient‐derived organoids (PDOs). Metabolomic analysis was applied to detect the enzyme activity. Transcriptome profiling was conducted to illustrate the anti‐HCC mechanism of oroxylin A. TKT knocking‐down HCC cell lines and PDOs were established to evaluate the role of TKT in oroxylin A‐induced HCC suppression. Results By targeting TKT, oroxylin A stabilised the protein to proteases and temperature extremes, decreased its activity and expression, resulted in accumulation of non‐oxidative PPP substrates, and activated p53 signalling. In addition, oroxylin A suppressed cell proliferation, induced apoptosis and cell‐cycle arrest, and inhibited the growth of human xenograft tumours and DEN‐induced HCC in mice. Crucially, TKT depletion exerted identical effects to oroxylin A, and the promising inhibitor also exhibited excellent therapeutic efficacy against clinically relevant HCC PDOs. Conclusions These results uncover a unique role for oroxylin A in TKT inhibition, which directly targets TKT and suppresses the non‐oxidative PPP. Our findings will facilitate the development of small‐molecule inhibitors of TKT and novel therapeutics for HCC.

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The role of transketolase in human cancer progression and therapy

Cited by 23 publications

References 142 publications

Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

In Situ Investigation of Intercellular Signal Transduction Based on Detection of Extracellular pH and ROS by Scanning Electrochemical Microscopy

Novel transketolase inhibitor oroxylin A suppresses the non‐oxidative pentose phosphate pathway and hepatocellular carcinoma tumour growth in mice and patient‐derived organoids

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