Expression of Pentose Phosphate Pathway-Related Proteins in Breast Cancer

Choi, Jong Myung; Kim, Eun Sol; Koo, Ja Seung

doi:10.1155/2018/9369358

Cited by 33 publications

(32 citation statements)

References 37 publications

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“…The inhibitory abilities of an interesting compound, GP269, were tested against 6-phospho-gluconolactonase (6PGL). While this inhibition was attempting to target Trypanosoma Brucei , this compound could also be a potential therapeutic tool for breast cancer, since 6PGL was found to be overexpressed in human epidermal growth factor receptor 2 (HER2) positive breast cancer cells [ 41 , 42 ].…”

Section: Oxidative Phasementioning

confidence: 99%

The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH

et al. 2020

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The Pentose Phosphate Pathway (PPP) is one of the key metabolic pathways occurring in living cells to produce energy and maintain cellular homeostasis. Cancer cells have higher cytoplasmic utilization of glucose (glycolysis), even in the presence of oxygen; this is known as the “Warburg Effect”. However, cytoplasmic glucose utilization can also occur in cancer through the PPP. This pathway contributes to cancer cells by operating in many different ways: (i) as a defense mechanism via the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to prevent apoptosis, (ii) as a provision for the maintenance of energy by intermediate glycolysis, (iii) by increasing genomic material to the cellular pool of nucleic acid bases, (iv) by promoting survival through increasing glycolysis, and so increasing acid production, and (v) by inducing cellular proliferation by the synthesis of nucleic acid, fatty acid, and amino acid. Each step of the PPP can be upregulated in some types of cancer but not in others. An interesting aspect of this metabolic pathway is the shared regulation of the glycolytic and PPP pathways by intracellular pH (pHi). Indeed, as with glycolysis, the optimum activity of the enzymes driving the PPP occurs at an alkaline pHi, which is compatible with the cytoplasmic pH of cancer cells. Here, we outline each step of the PPP and discuss its possible correlation with cancer.

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Section: Oxidative Phasementioning

confidence: 99%

The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH

et al. 2020

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“…Further, NRF2 regulates the expression of the SLC7A11 (subunit of the cystine/glutamate antiporter system Xc − ), which imports cystine into cells in exchange for glutamate, and hence, regulates cysteine and glutamate availability in cells ( 163 ). Finally, NRF2 regulates the pentose-phosphate shunt and through that NADPH availability that is needed for reducing GSSG ( 4 , 35 , 92 , 159 , 334 ).…”

Section: The Molecular Determinants Of Nrf2 Signalingmentioning

confidence: 99%

“…NRF2-dependent G6pd/HIF-1α activation elicits Notch1 signaling by upregulating Jagged1 and Hes1, and, thereby, promoting epithelial-mesenchymal transition (EMT) in breast cancer cells ( 334 ). In addition, a clinical study showed that PPP-related proteins are differentially expressed according to the molecular subtype of breast cancer; in particular, G6pd and 6-phosphogluconolactone are highly expressed in HER2-type breast cancer ( 35 ). Thus, understanding the role of this pathway in breast cancers, including the effects of targeting this pathway, is needed to clarify the clinical implications of PPP in breast cancers.…”

Section: Role Of Nrf2 In Cancermentioning

confidence: 99%

Nuclear Factor Erythroid 2-Related Factor 2 in Regulating Cancer Metabolism

Smolková

Mikó

Kovàcs

et al. 2020

Antioxidants & Redox Signaling

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Significance: Nuclear factor erythroid 2 (NFE2)-related factor 2 (NFE2L2, or NRF2) is a transcription factor predominantly affecting the expression of antioxidant genes. NRF2 plays a significant role in the control of redox balance, which is crucial in cancer cells. NRF2 activation regulates numerous cancer hallmarks, including metabolism, cancer stem cell characteristics, tumor aggressiveness, invasion, and metastasis formation. We review the molecular characteristics of the NRF2 pathway and discuss its interactions with the cancer hallmarks previously listed. Recent Advances: The noncanonical activation of NRF2 was recently discovered, and members of this pathway are involved in carcinogenesis. Further, cancer-related changes (e.g., metabolic flexibility) that support cancer progression were found to be redox-and NRF2 dependent. Critical Issues: NRF2 undergoes Janus-faced behavior in cancers. The pro-or antineoplastic effects of NRF2 are context dependent and essentially based on the specific molecular characteristics of the cancer in question. Therefore, systematic investigation of NRF2 signaling is necessary to clarify its role in cancer etiology. The biggest challenge in the NRF2 field is to determine which cancers can be targeted for better clinical outcomes. Further, large-scale genomic and transcriptomic studies are missing to correlate the clinical outcome with the activity of the NRF2 system. Future Directions: To exploit NRF2 in a clinical setting in the future, the druggable members of the NRF2 pathway should be identified. In addition, it will be important to study how the modulation of the NRF2 system interferes with cytostatic drugs and their combinations. Antioxid. Redox Signal. 00, 000-000.

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“…In terms of targeted, personalized therapy, it is desirable to take such differences into account. In the case of the pentose phosphate pathway (PPP), it has been shown that PPP-associated proteins, such as 6PGL, 6PGDH, or NRF2, are not differentially expressed among breast cancer subtypes but are overexpressed relative to control samples (46). Glucose 6-phosphate dehydrogenase G6PD has been closely associated with prognosis in Basal tumors (47).…”

Section: Luminal B Tumors Present Higher Pathway Deregulation Scoresmentioning

confidence: 99%

Targeting Metabolic Deregulation Landscapes in Breast Cancer Subtypes

2020

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Metabolic deregulation is an emergent hallmark of cancer. Altered patterns of metabolic pathways result in exacerbated synthesis of macromolecules, increased proliferation, and resistance to treatment via alteration of drug processing. In addition, molecular heterogeneity creates a barrier to therapeutic options. In breast cancer, this broad variation in molecular metabolism constitutes, simultaneously, a source of prognostic and therapeutic challenges and a doorway to novel interventions. In this work, we investigated the metabolic deregulation landscapes in breast cancer molecular subtypes. Such landscapes are the regulatory signatures behind subtype-specific metabolic features. n = 735 breast cancer samples of the Luminal A, Luminal B, Her2+, and Basal subtypes, as well as n = 113 healthy breast tissue samples were analyzed. By means of a single-sample-based algorithm, deregulation for all metabolic pathways in every sample was determined. Deregulation levels match almost perfectly with the molecular classification, indicating that metabolic anomalies are closely associated with gene-expression signatures. Luminal B tumors are the most deregulated but are also the ones with higher within-subtype variance. We argued that this variation may underlie the fact that Luminal B tumors usually present the worst prognosis, a high rate of recurrence, and the lowest response to treatment in the long term. Finally, we designed a therapeutic scheme to regulate purine metabolism in breast cancer, independently of the molecular subtype. This scheme is founded on a computational tool that provides a set of FDA-approved drugs to target pathway-specific differentially expressed genes. By providing metabolic deregulation patterns at the single-sample level in breast cancer subtypes, we have been able to further characterize tumor behavior. This approach, together with targeted therapy, may open novel avenues for the design of personalized diagnostic, prognostic, and therapeutic strategies.

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Expression of Pentose Phosphate Pathway-Related Proteins in Breast Cancer

Cited by 33 publications

References 37 publications

The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH

The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH

Nuclear Factor Erythroid 2-Related Factor 2 in Regulating Cancer Metabolism

Targeting Metabolic Deregulation Landscapes in Breast Cancer Subtypes

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