Augmented Pentose Phosphate Pathway Plays Critical Roles in Colorectal Carcinomas

Shibuya, Norisuke; Inoue, Kazuhiro; Tanaka, Genki; Akimoto, Kazumi; Kubota, Keiichi

doi:10.1159/000369905

Cited by 25 publications

(22 citation statements)

References 35 publications

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“…and ), suggesting that CTOSs are more resilient against thioredoxin inhibition due to NRF2 feedback. Pharmacological inhibition of critical enzyme for PPP (G6PD) had negligible effects in terms of NRF2 feedback, with the exception of TXNRD1 induction at 24 h. Previously, we found that G6PD inhibitor CB83 reproducibly decreased NADPH/NADP + ratios, but failed to alter GSH/GSSG ratios in CRC cell lines . While the compensation mechanisms remain unknown, other NADPH production pathway could be involved in NRF2‐independent manner.…”

Section: Discussionmentioning

confidence: 92%

“…Using patient‐derived colorectal CTOSs and their xenografts , we made several discoveries. First, five GST isoforms ( GSTA1, A2, M4, O2, and P1 ) are up‐regulated in colorectal CTOSs relative to fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Using patient-derived colorectal CTOSs and their xenografts [10], we made several discoveries. First, five GST Figure 7.…”

Section: Discussionmentioning

confidence: 99%

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Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells

et al. 2016

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NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S‐transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft‐derived spheroids than in fibroblasts. Piperlongumine (2.5–10 μmol/L) and auranofin (0.25–4 μmol/L) were used to inhibit glutathione S‐transferase π and thioredoxin reductase, respectively. Piperlongumine or auranofin alone up‐regulated the expression of NRF2 target genes, but not TP53 targets. While piperlongumine showed modest cancer‐specific cell killing (IC 50 difference between cancer spheroids and fibroblasts: P = 0.052), auranofin appeared more toxic to fibroblasts (IC 50 difference between cancer spheroids and fibroblasts: P = 0.002). The synergism of dual inhibition was evaluated by determining the Combination Index, based on the number of surviving cells with combination treatments. Molar ratios indicated synergism in cancer spheroids, but not in fibroblasts: (auranofin:piperlongumine) = 2:5, 1:5, 1:10, and 1:20. Cancer‐specific cell killing was achieved at the following drug concentrations (auranofin:piperlongumine): 0.25:2.5 μmol/L, 0.5:2.5 μmol/L, or 0.25:5 μmol/L. The dual inhibition successfully decreased CD44v9 surface presentation and delayed tumor emergence in nude mouse. However, a small subpopulation persistently survived and accumulated phosphorylated histone H2A. Such “persisters” still retained lesser but significant tumorigenicity. Thus, dual inhibition of glutathione S‐transferase π and thioredoxin reductase could be a feasible option for decreasing the tumor mass and CD44v9‐positive fraction by disrupting redox regulation.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells

et al. 2016

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“…In most types of human cancers, PPP is over-activated1819. Additionally, G-6-P dehydrogenase (G6PD) was reported to be activated by c-Src20.…”

Section: Resultsmentioning

confidence: 99%

c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

et al. 2017

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It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis. Tyrosine phosphorylation dramatically increases their catalytic activity and thus enhances glycolysis. Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. Mutation in c-Src phosphorylation site of either HK1 or HK2 remarkably abrogates the stimulating effects of c-Src on glycolysis, cell proliferation, migration, invasion, tumorigenesis and metastasis. Due to its lower Km for glucose, HK1 rather than HK2 is required for tumour cell survival when glucose is scarce. Importantly, HK1-Y732 phosphorylation level remarkably correlates with the incidence and metastasis of various clinical cancers and may serve as a marker to predict metastasis risk of primary cancers.

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“…Xu et al (51) provided intimated the importance of the TKT-like 1 (TKTL1; one TKT isoform) dysregulation in human HCT116 colon carcinoma cells and indicated that TKTL1 overexpression may be considered as a novel tumor marker, as well as a promising target for anticancer therapy. Furthermore, Shibuya et al (52) reported that the synthesis of glycolytic and PPP enzymes is almost ubiquitously augmented in colorectal carcinoma specimens and that pharmacological inhibition of the mechanistic target of rapamycin (mTOR)-PPP axis presents a promising therapeutic strategy against CRCs.…”

Section: Numerous Novel Glucose Metabolism Mechanisms Involve Mirna Rmentioning

confidence: 99%

Advances in glucose metabolism research in colorectal cancer

Fang

Xiao

2016

Biomedical Reports

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Cancer cells uptake glucose at a higher rate and produce lactic acid rather than metabolizing pyruvate through the tricarboxylic acid cycle. This adaptive metabolic shift is termed the Warburg effect. Recently progress had been made regarding the mechanistic understanding of glucose metabolism and associated diagnostic and therapeutic methods, which have been investigated in colorectal cancer. The majority of novel mechanisms involve important glucose metabolism associated genes and miRNA regulation. The present review discusses the contribution of these research results to facilitate with the development of novel diagnosis and anticancer treatment options.

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Augmented Pentose Phosphate Pathway Plays Critical Roles in Colorectal Carcinomas

Cited by 25 publications

References 35 publications

Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells

Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells

c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

Advances in glucose metabolism research in colorectal cancer

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