Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions and redox balance. NADPH homeostasis is regulated by varied signaling pathways and several metabolic enzymes that undergo adaptive alteration in cancer cells. The metabolic reprogramming of NADPH renders cancer cells both highly dependent on this metabolic network for antioxidant capacity and more susceptible to oxidative stress. Modulating the unique NADPH homeostasis of cancer cells might be an effective strategy to eliminate these cells. In this review, we summarize the current existing literatures on NADPH homeostasis, including its biological functions, regulatory mechanisms and the corresponding therapeutic interventions in human cancers, providing insights into therapeutic implications of targeting NADPH metabolism and the associated mechanism for cancer therapy.

/pdf/nadph-homeostasis-in-cancer-functions-mechanisms-and-2cpyfn0evc.pdf

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

Hypoxia Induces Drug Resistance in Colorectal Cancer through the HIF-1α/miR-338-5p/IL-6 Feedback Loop

Certain subtypes of cancer cells require oxidative phosphorylation (OXPHOS) to survive. Increased OXPHOS dependency is frequently a hallmark of cancer stem cells and cells resistant to chemotherapy and targeted therapies. Suppressing the OXPHOS function might also influence the tumor microenvironment by alleviating hypoxia and improving the antitumor immune response. Thus, targeting OXPHOS is a promising strategy to treat various cancers. A growing arsenal of therapeutic agents is under development to inhibit this biological process. This Perspective provides an overview of the structure and function of OXPHOS complexes, their biological functions in cancer, relevant research tools and models, as well as the limitations of OXPHOS as drug targets. We also focus on the current development status of OXPHOS inhibitors and potential therapeutic strategies to strengthen their clinical applications.

Why All the Fuss about Oxidative Phosphorylation (OXPHOS)

Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify ERO1L as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo. Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18F-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.

Endoplasmic Reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in Pancreatic Cancer.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/1878-0261.12182

IDH2 is a novel diagnostic and prognostic serum biomarker for non-small-cell lung cancer.

Nucleoporin 37 kDa (NUP37), a member of the nucleoporin family, has been reported to regulate the proliferation and apoptosis of several tumor types. However, its role in the tumor immune microenvironment is unclear. Here, we evaluated the expression, methylation, copy number alteration, and prognostic significance of NUP37 using RNA-seq and clinical data from The Cancer Genome Atlas. We observed higher expression of NUP37 in 28 of 29 tumor types, and high NUP37 expression predicted worse survival status of patients in 15 tumors. Using data from the cBioportal database, we described the gene variation of NUP37 in glioma and pan-cancer. We further assessed the role of NUP37 in the tumor immune microenvironment using immune infiltration data. NUP37 expression was positively associated with the infiltration levels of immunosuppressive cells, such as nTregs, iTregs, and tumor-associated macrophages, and negatively correlated with immune killer cells, such as CD8+ T and NK cells across cancers. Furthermore, NUP37 expression was associated with immune checkpoints and immune regulation-related genes. The half-maximal inhibitory concentrations of anti-cancer drugs were obtained from the Genomics of Drug Sensitivity in the Cancer database. The correlation between half-maximal inhibitory concentration and NUP37 expression was evaluated. The patients with the evaluated expression of NUP37 were resistant to several anti-cancer drugs. These results suggest that NUP37 is a potential oncogene and prognostic biomarker in glioma and pan-cancer. Tumor tissues with high NUP37 expression exist in a relatively immunosuppressive microenvironment and are resistant to several anti-cancer drugs.

/pdf/pan-cancer-analysis-reveals-nup37-as-a-prognostic-biomarker-2dgj40sf.pdf

Pan-cancer analysis reveals NUP37 as a prognostic biomarker correlated with the immunosuppressive microenvironment in glioma

Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers. However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown. Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer. Methods: Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples. IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients. The biological functions of IDH2 were evaluated by using cell-based assays and in vivo xenograft mouse models. Results: Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers. Targeting IDH2 with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth. Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation. Conclusion: IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.

Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer.

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IDH2 is a novel diagnostic and prognostic serum biomarker for non-small-cell lung cancer.

Pan-cancer analysis reveals NUP37 as a prognostic biomarker correlated with the immunosuppressive microenvironment in glioma

Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer.