Are we still on the right path(way)?: the altered expression of the pentose phosphate pathway in solid tumors and the potential of its inhibition in combination therapy

ABSTRACT

Introduction

The pentose phosphate pathway (PPP) branches from glycolysis and is crucial for cell growth, since it provides necessary compounds for anabolic reactions, nucleotide synthesis, and detoxification of reactive-oxygen-species (ROS). Overexpression of PPP enzymes has been reported in multiple cancer types and linked to therapy resistance, making their inhibition interesting targets for anti-cancer therapies.

Areas covered

This review summarizes the extent of PPP upregulation across different cancer types, and the non-metabolic functions that PPP-enzymes might contribute to cancer initiation and maintenance. The effects of PPP-inhibition and their combinations with chemotherapeutics are summarized. We searched the databases provided by the University of Amsterdam to characterize the altered expression of the PPP across different cancer types, and to identify the effects of PPP-inhibition.

Expert opinion

It can be concluded that there are synergistic and additive effects of PPP-inhibition and various classes of chemotherapeutics. These effects may be attributed to the increased susceptibility to ROS. However, the toxicity, low efficacy, and off-target effects of PPP-inhibitors make application in clinical practice challenging. Novel inhibitors are currently being developed, which could make PPP-inhibition a potential therapeutic strategy in the future, especially in combination with conventional chemotherapeutics and the inhibition of other metabolic pathways.

KEYWORDS:

• Pentose phosphate pathway
• glycolysis
• cancer
• NAD/NADH
• chemotherapy

Article highlights

• Altered expression of enzymes in the Pentose Phosphate Pathway (PPP) has been reported in various types of solid tumors, although the timing and extent of expression may differ per cancer type.

• Overexpression of PPP-enzymes has been associated with altered responses toward different classes of therapies, both targeted therapies and commonly used chemotherapeutic agents.

• In addition to catalyzing metabolic reactions, PPP-enzymes may play a role in cancer initiation by participating in non-metabolic functions, for example, by inducing STAT-3 activity, by contributing to β-catenin stabilization and by interacting with EGFR/MAPK signaling.

• Inhibition and knockdown of PPP-enzymes may reduce proliferation and induce apoptosis in different model systems. Inhibition and knockdown have also been associated with reductions in migration and invasion, and upregulation of anti-metastatic genes. Additionally, it may alter the flux through metabolic pathways (such as glutaminolysis and glycolysis), as well as interfere with nucleotide synthesis.

• Inhibition and knockdown of PPP-enzymes has been associated with AMPK-activation, PP2A-activation, impaired folate metabolism, and HIF-1α degradation.

• Some of the additive and synergistic effects of combining PPP-inhibition with platin-based compounds, taxanes, anthracyclines, and antimetabolites have already been established in the 80s and 90s. Most of these effects appear to be linked to the increased susceptibility of cells to oxidative stress upon PPP-inhibition. Additionally, enhanced activation of, for example, 5-FU due to PRPP-accumulation following PPP-inhibition could potentially lead to possible additive/and/or synergistic effects. Especially, in combination with chemotherapeutic agents and inhibitors of other metabolic pathways, PPP-inhibition could become a promising strategy in cancer treatment.

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Abbreviations

5-FU: 5-fluorouracil; 6-PG: 6-phosphogluconate; 6PGD: 6-phosphogluconate dehydrogenase; 6PGL: 6-phosphogluconolactone; 6PGLS: 6-phosphogluconolactonase; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; CRC: colorectal carcinoma; G6PD: glucose-6-phosphate dehydrogenase; GSH: glutathione; GSTP1: Glutathione S-transferase P1; HCC: hepatocellular carcinoma; HIF-1α: hypoxia-inducible factor 1 alpha; HNSC: head and neck squamous cell carcinoma; JNK: c-Jun N-terminal kinase; LKB1: liver kinase B1; NAD: nicotinamide adenine dinucleotide; NADPH: nicotinamide-adenine dinucleotide phosphate; Non-ox-PPP: non-oxidative pentose phosphate pathway; NRF2: nuclear factor, erythroid 2-like 2; NSCLC: non-small cell lung cancer; Ox-PPP: oxidative pentose phosphate pathway; PDAC: pancreatic ductal adenocarcinoma; PPP: pentose phosphate pathway; PRPP: phosphoribosyl pyrophosphate; PTEN: phosphatase and tensin homolog; R-5-P: ribose-5-phosphate; ROS: Reactive oxygen species; RPE: ribulose-phosphate-epimerase; RPI: ribulose-phosphate-isomerase; Ru-5-P: ribulose-5-phosphate; SOD2: superoxide dismutase 2; TALDO: transaldolase; TKT: transketolase; TKTL1: transketolase-like protein 1; TKTL2: transketolase-like protein 2.

Declaration of interest

GJ Peters received consultancy fees/travel compensation from Clear Creek Bio Inc, Isofol Medical AB, Ellipses Pharma, and Taiho Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Science Center (grants were received from: OPUS Project 2018/31/B/NZ7/02909 [2019.08.21; MF, GJP, RTS]; IDUB 664/256/62- 0212 [GJP, RTS]; and AIRC IG-24444/MIUR 2018 and KWF grant 11897 [EG]).