The Pentose Phosphate Pathway as a Potential Target for Cancer Therapy

Cho, Eunae Sandra; Hoon, Yong; Kim, Hyun Sil; Kim, Nam Hee; Yook, Jong In

doi:10.4062/biomolther.2017.179

Cited by 137 publications

(123 citation statements)

References 61 publications

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“…**P < 0.01 compared to untreated cells3.2 | Effect of Nrf2 on pentose phosphate pathway in breast cancer cellsPentose phosphate pathway (PPP) is a major glucose metabolism pathway, which is fundamental in cancer growth and metastasis 19. Nrf2-specific shRNA or overexpression of Nrf2 caused a decrease in Nrf2 mRNA and protein expression in MCF-7 and MDA-MB-231 cells.…”

mentioning

confidence: 99%

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

Zhang

et al. 2019

J Cellular Molecular Medi

146

100

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Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF‐E2‐related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch‐like ECH‐associated protein 1 (Keap1) reduced the expression of glucose‐6‐phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia‐inducing factor 1α (HIF‐1α) in MCF‐7 and MDA‐MB‐231 cells. Overexpression of Nrf2 up‐regulated the expression of Notch1 via G6PD/HIF‐1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES‐1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2‐driven breast cancer metastasis.

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confidence: 99%

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

Zhang

et al. 2019

J Cellular Molecular Medi

146

100

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“…Therefore, a decreased activity of this pathway will impair proliferation and defence against oxidative stress, and it has been discussed that the PPP could be in fact a potential target for cancer therapy. 32 In previous investigations, the anti-neoplastic of carnosine was shown to be associated with decreased ATP production. However, there have been different reports either pointing towards an effect on glycolysis, mitochondrial respiration or on both, depending on the cell type investigated.…”

Section: Discussionmentioning

confidence: 93%

“…The PPP is especially important for tumour cells as it provides nucleotides for nucleic acid synthesis and NADPH required for fatty acid synthesis and scavenging of reactive oxygen species (for review see). Therefore, a decreased activity of this pathway will impair proliferation and defence against oxidative stress, and it has been discussed that the PPP could be in fact a potential target for cancer therapy …”

Section: Discussionmentioning

confidence: 99%

Non‐enzymatic reaction of carnosine and glyceraldehyde‐3‐phosphate accompanies metabolic changes of the pentose phosphate pathway

et al. 2019

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Objectives Carnosine (β‐alanyl‐l‐histidine) is a naturally occurring dipeptide that selectively inhibits cancer cell growth, possibly by influencing glucose metabolism. As its precise mode of action and its primary targets are unknown, we analysed carnosine's effect on metabolites and pathways in glioblastoma cells. Materials and methods Glioblastoma cells, U87, T98G and LN229, were treated with carnosine, and metabolites were analysed by gas chromatography coupled with mass spectrometry. Furthermore, mitochondrial ATP production was determined by extracellular flux analysis and reaction products of carnosine were investigated using mass spectrometry. Results Carnosine decreased the intracellular abundance of several metabolites indicating a reduced activity of the pentose phosphate pathway, the malate‐aspartate shuttle and the glycerol phosphate shuttle. Mitochondrial respiration was reduced in U87 and T98G but not in LN229 cells, independent of whether glucose or pyruvate was used as substrate. Finally, we demonstrate non‐enzymatic reaction of carnosine with dihydroxyacetone phosphate and glyceraldehyde‐3‐phosphate. However, glycolytic flux from glucose to l‐lactate appeared not to be affected by the reaction of carnosine with the metabolites. Conclusions Carnosine reacts non‐enzymatically with glycolytic intermediates reducing the activity of the pentose phosphate pathway which is required for cell proliferation. Although the activity of the malate‐aspartate and the glycerol phosphate shuttle appear to be affected, reduced mitochondrial ATP production under the influence of the dipeptide is cell‐specific and appears to be independent of the effect on the shuttles.

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“…One major mechanism for enhancing ROS levels in cancer cells occurs via a feedback amplification loop involving ROS‐mediated increase in cytosolic NADPH production. Thus, metabolic profiling and other studies described below have shown for many cancer cell types that glycolysis is partly shunted via Glc6PDH into the oxidative PPP branch leading to this being proposed as a target for cancer therapy . In fact, studies of human skin cells revealed that hypoxia increased ROS (such as H 2 O 2 ) directly and rapidly increased the activity of the PPP as a first‐line defense against ensuing oxidative stress and which was alleviated via increased NADPH production essential to prevent against oxidative damage .…”

Section: Introductionmentioning

confidence: 98%

“…More importantly, PPP activation also serves the additional purpose of ensuring a continuing NADPH production required for TrxR1 function as a critical antioxidant system in advanced stage cancer cells and CSCs . The mechanisms of metabolic reprogramming in metastatic cancer cells and roles for mut‐p53/ nuclear respiratory factor 2 (NRF2) and HIF‐1, as well as the importance of the NADPH/TrxR axis in advanced stage cancer cell metabolism have been previously reviewed and are not further discussed here .…”

Section: Introductionmentioning

confidence: 99%

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

Ralph

Nozuhur

ALHulais

et al. 2019

Medicinal Research Reviews

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Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases. The focus here is to explore the repurposing of old drugs that cause pro‐oxidative overload to overcome onset of resistance to chemotherapy and enhance chemotherapeutic responses, particularly against metastatic cancer. Excellent examples of US Food and Drug Administration approved drugs suitable for repurposing are the potent and specific thioreductase inhibitor auranofin and the nonsteroidal anti‐inflammatory drug, celecoxib. Recently, both drugs were shown to selectively target and kill metastatic cancer cells and cancer stem cells (CSCs), predominantly by promoting excessive mitochondrial reactive oxygen species. Thus, targeting intracellular redox systems of advanced stage metastatic cancer cells and CSCs can promote an overload of pro‐oxidative stress to activate the intrinsic pathway for programmed cell death. It is envisaged that more clinical studies will incorporate longer term use of repurposed drugs, such as auranofin or celecoxib, to target redox systems in cancer cells as part of common practice postcancer diagnosis, providing enhanced chemotherapeutic responses and increased cancer survival.

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The Pentose Phosphate Pathway as a Potential Target for Cancer Therapy

Cited by 137 publications

References 61 publications

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

Non‐enzymatic reaction of carnosine and glyceraldehyde‐3‐phosphate accompanies metabolic changes of the pentose phosphate pathway

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

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