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

Li, Jiangjiang; He, Ya; Tan, Zhongping; Lu, Jinmiao; Li, Liling; Song, Xin; Shi, Feng; Xie, Longlong; You, Sylvaine; Luo, Xiangjian; Li, Namei; Li, Yueshuo; Liu, Xiaolan; Tang, Min; Weng, Xiaole; Yi, Wei; Fan, Jia; Zhou, Jian; Gao, Qiang; Qiu, Shuang; Wu, Wei‐Zhong; Bode, Ann M.; Cao, Ya

doi:10.7150/thno.21524

Cited by 61 publications

(63 citation statements)

References 47 publications

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“…Moreover, a close correlation was found between ERO1L expression and glycolytic components, including glucose transporter, glycolytic enzymes, and lactate transporter ( Figure S3 ). The Warburg effect can enable rapid cell proliferation by providing abundant cellular buildings for biosynthetic pathways, including nucleotides, lipids, and nonessential amino acids 29 - 31 . Therefore, we investigated whether the effect of ERO1L on PDAC is associated with its ability to modulate the Warburg effect.…”

Section: Resultsmentioning

confidence: 99%

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

Zhang¹,

Yang²,

Lin³

et al. 2020

Theranostics

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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 18 F-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.

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Section: Resultsmentioning

confidence: 99%

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

Zhang¹,

Yang²,

Lin³

et al. 2020

Theranostics

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“…Immunohistochemistry was performed on 2.5–3.0‐μm formalin‐fixed, paraffin‐embedded (FFPE) whole‐tissue sections, as described in previous studies 13–19 . Briefly, antigens were retrieved in a pressure cooker for 2.5 min.…”

Section: Methodsmentioning

confidence: 99%

Frequent KRAS mutations in oncocytic papillary renal neoplasm with inverted nuclei

Tong

Zhu

et al. 2020

Histopathology

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Aims: Papillary renal neoplasm with reverse polarity (PRNRP) is a newly documented rare tumour type. Its molecular pathological features have thus far been very little studied. Methods and results: There were 13 PRNRP cases including 3 The Cancer Genome Atlas (TCGA) cases and our 10 cases in this study. The 3 TCGA cases were found by a combined analysis of GATA3 mRNA expression levels and digital slides from the TCGA papillary renal cell carcinoma project. KRAS codon 12 mutations were identified in the three PRNRPs from TCGA. Of our 10 PRNRP cases, the mutations were also discovered using Sanger sequencing in seven (77.8%) of nine cases with available DNA, where KRAS p.G12V (n = 3), p.G12D (n = 2), p.G12R (n = 1) and p.G12C (n = 1) alterations were found. PRNRP shared similar gene expression profiles with renal distal tubules via an interprofile correlation analysis. Gene set enrichment analysis revealed that genes involved in 'KEGG aldosterone regulated sodium reabsorption' or 'hallmark apical surface' were enriched in PRNRP. Moreover, polarised immunostaining patterns for L1CAM and EMA in the distal tubule were maintained in PRNRP. Conclusions: These results imply that the tumour potentially originates from the distal tubule, especially from the cortical collecting duct, and probably retains its cell polarity, except for nuclear inversion. We therefore propose that oncocytic papillary renal neoplasm with inverted nuclei (OPR-NIN) is a better name for this tumour type. OPRNIN is a kidney site-specific KRAS mutation neoplasm different from conventional papillary renal cell carcinoma.

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“…129 Specially, studies also found that IDH1 is significantly downregulated in clear cell renal cell carcinoma (ccRCC) compared with normal kidney cells, suggesting that IDH1 may function as a candidate tumor suppressor for ccRCC. 130,131 Most studies indicate that IDH2 is also significantly upregulated in ESCC, 132 ovarian cancer, 133 lung cancer and other types of cancer, 134 playing a pro-oncogenic role. Overexpression of IDH2 decreases ROS levels and increases cancer cell growth.…”

Section: Pentose Phosphate Pathwaymentioning

confidence: 99%

“…Most studies indicate that IDH2 is also significantly upregulated in ESCC, 132 ovarian cancer, 133 lung cancer and other types of cancer, 134 playing a pro-oncogenic role. Overexpression of IDH2 decreases ROS levels and increases cancer cell growth.…”

Section: Molecular Mechanisms Of Nadph Homeostasis In Cancermentioning

confidence: 99%

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

Lin

Tian

et al. 2020

Sig Transduct Target Ther

263

196

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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.

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

Cited by 61 publications

References 47 publications

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

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

Frequent KRAS mutations in oncocytic papillary renal neoplasm with inverted nuclei

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

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