ALOX5‐5‐HETE promotes gastric cancer growth and alleviates chemotherapy toxicity via MEK/ERK activation

Tang, Jianjun; Zhang, Chuang; Lin, Jingjing; Duan, Peng; Long, Jian; Zhu, Hongyan

doi:10.1002/cam4.4066

Cited by 26 publications

(14 citation statements)

References 29 publications

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“…ALOX5 was shown to regulate ferroptosis in cancer cells through lipid peroxidation ( 19 , 63 ). In gastric cancer and hepatocellular carcinoma, ALOX5 expression was significantly higher than that in normal tissues in the promotion of tumor progression ( 64 , 65 ). On the other hand, ALOX5 inhibition augments the efficacy of other chemotherapeutic agents in the treatment of gastric cancer.…”

Section: Discussionmentioning

confidence: 97%

Identification and Validation in a Novel Quantification System of Ferroptosis Patterns for the Prediction of Prognosis and Immunotherapy Response in Left- and Right-Sided Colon Cancer

Zhang

Deng

et al. 2022

Front. Immunol.

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BackgroundThis study aimed to establish a novel quantification system of ferroptosis patterns and comprehensively analyze the relationship between ferroptosis score (FS) and the immune cell infiltration (ICI) characterization, tumor mutation burden (TMB), prognosis, and therapeutic sensitivity in left-sided and right-sided colon cancers (LCCs and RCCs, respectively).MethodsWe comprehensively evaluated the ferroptosis patterns in 444 LCCs and RCCs based on 59 ferroptosis-related genes (FRGs). The FS was constructed to quantify ferroptosis patterns by using principal component analysis algorithms. Next, the prognostic value and therapeutic sensitivities were evaluated using multiple methods. Finally, we performed weighted gene co-expression network analysis (WGCNA) to identify the key FRGs. The IMvigor210 cohort, TCGA-COAD proteomics cohort, and Immunophenoscores were used to verify the predictive abilities of FS and the key FRGs.ResultsTwo ferroptosis clusters were determined. Ferroptosis cluster B demonstrated a high degree of congenital ICI and stromal-related signal enrichment with a poor prognosis. The prognosis, response of targeted inhibitors, and immunotherapy were significantly different between high and low FS groups (HSG and LSG, respectively). HSG was characterized by high TMB and microsatellite instability-high subtype with poor prognosis. Meanwhile, LSG was more likely to benefit from immunotherapy. ALOX5 was identified as a key FRG based on FS. Patients with high protein levels of ALOX5 had poorer prognoses.ConclusionThis work revealed that the evaluation of ferroptosis subtypes will contribute to gaining insight into the heterogeneity in LCCs and RCCs. The quantification for ferroptosis patterns played a non-negligible role in predicting ICI characterization, prognosis, and individualized immunotherapy strategies.

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Section: Discussionmentioning

confidence: 97%

Identification and Validation in a Novel Quantification System of Ferroptosis Patterns for the Prediction of Prognosis and Immunotherapy Response in Left- and Right-Sided Colon Cancer

Zhang

Deng

et al. 2022

Front. Immunol.

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“…Among the 8-gene signature of high immune cell infiltration (type C2), ALOX5 has been found to promote gastric cancer growth and attenuate chemotherapy toxicity [63], while in breast cancer, ALOX5 activation is associated with HER2 expression as well as mediates breast cancer growth and migration [64]. Recent studies have reported that the polymorphism of FCGR2A expression is associated with an increased risk of lung cancer [65].…”

Section: Discussionmentioning

confidence: 99%

“…The pathway with the largest number of associated genes is the mitogen-activated protein kinases (MAPKs) signaling pathway. Eight genes could regulate it, and they are AKAP2 [72], ALOX5 [63], GCGR [73], NLRP12 [74], NTSR1 [75], PF4 [76], SIGLEC12 [68] and TGM2 [77]. Wnt/β-catenin signaling pathway could be regulated by AKAP2 [55], ALOX5 [78] and TGM2 [79].…”

Section: Discussionmentioning

confidence: 99%

Construction of a predictive model for immunotherapy efficacy in lung squamous cell carcinoma based on the degree of tumor-infiltrating immune cells and molecular typing

et al. 2022

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Background To construct a predictive model of immunotherapy efficacy for patients with lung squamous cell carcinoma (LUSC) based on the degree of tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME). Methods The data of 501 patients with LUSC in the TCGA database were used as a training set, and grouped using non-negative matrix factorization (NMF) based on the degree of TIIC assessed by single-sample gene set enrichment analysis (GSEA). Two data sets (GSE126044 and GSE135222) were used as validation sets. Genes screened for modeling by least absolute shrinkage and selection operator (LASSO) regression and used to construct a model based on immunophenotyping score (IPTS). RNA extraction and qPCR were performed to validate the prognostic value of IPTS in our independent LUSC cohort. The receiver operating characteristic (ROC) curve was constructed to determine the predictive value of the immune efficacy. Kaplan–Meier survival curve analysis was performed to evaluate the prognostic predictive ability. Correlation analysis and enrichment analysis were used to explore the potential mechanism of IPTS molecular typing involved in predicting the immunotherapy efficacy for patients with LUSC. Results The training set was divided into a low immune cell infiltration type (C1) and a high immune cell infiltration type (C2) by NMF typing, and the IPTS molecular typing based on the 17-gene model could replace the results of the NMF typing. The area under the ROC curve (AUC) was 0.82. In both validation sets, the IPTS of patients who responded to immunotherapy were significantly higher than those who did not respond to immunotherapy (P = 0.0032 and P = 0.0451), whereas the AUC was 0.95 (95% CI = 1.00–0.84) and 0.77 (95% CI = 0.58–0.96), respectively. In our independent cohort, we validated its ability to predict the response to cancer immunotherapy, for the AUC was 0.88 (95% CI = 1.00–0.66). GSEA suggested that the high IPTS group was mainly involved in immune-related signaling pathways. Conclusions IPTS molecular typing based on the degree of TIIC in the TME could well predict the efficacy of immunotherapy in patients with LUSC with a certain prognostic value.

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“…Fig 1 shows the increase of some metabolites, ARA included, which were positively or negatively impacted by the CRC spheroid in the presence of adipocytes. Furthermore, studies demonstrate the increase of 5-lipoxygenase (5-LOX), part of the ARA pathway, and its metabolite, 5-HETE, in tumor tissues of the prostate, pancreas, colon, stomach and cervix [41][42][43][44][45][46].…”

Section: Plos Onementioning

confidence: 99%

Liquid chromatography coupled to high-resolution mass spectrometry metabolomics: A useful tool for investigating tumor secretome based on a three-dimensional co-culture model

et al. 2022

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Three-dimensional (3D) cell culture technologies, which more closely mimic the complex microenvironment of tissue, are being increasingly evaluated as a tool for the preclinical screening of clinically promising new molecules, and studying of tissue metabolism. Studies of metabolites released into the extracellular space (secretome) allow understanding the metabolic dynamics of tissues and changes caused by therapeutic interventions. Although quite advanced in the field of proteomics, studies on the secretome of low molecular weight metabolites (< 1500 Da) are still very scarce. We present an untargeted metabolomic protocol based on the hybrid technique of liquid chromatography coupled with high-resolution mass spectrometry for the analysis of low-molecular-weight metabolites released into the culture medium by 3D cultures and co-culture (secretome model). For that we analyzed HT-29 human colon carcinoma cells and 3T3-L1 preadipocytes in 3D-monoculture and 3D-co-culture. The putative identification of the metabolites indicated a sort of metabolites, among them arachidonic acid, glyceric acid, docosapentaenoic acid and beta-Alanine which are related to cancer and obesity. This protocol represents a possibility to list metabolites released in the extracellular environment in a comprehensive and untargeted manner, opening the way for the generation of metabolic hypotheses that will certainly contribute to the understanding of tissue metabolism, tissue-tissue interactions, and metabolic responses to the most varied interventions. Moreover, it brings the potential to determine novel pathways and accurately identify biomarkers in cancer and other diseases. The metabolites indicated in our study have a close relationship with the tumor microenvironment in accordance with the literature review.

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ALOX5‐5‐HETE promotes gastric cancer growth and alleviates chemotherapy toxicity via MEK/ERK activation

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 26 publications

References 29 publications

Identification and Validation in a Novel Quantification System of Ferroptosis Patterns for the Prediction of Prognosis and Immunotherapy Response in Left- and Right-Sided Colon Cancer

Identification and Validation in a Novel Quantification System of Ferroptosis Patterns for the Prediction of Prognosis and Immunotherapy Response in Left- and Right-Sided Colon Cancer

Construction of a predictive model for immunotherapy efficacy in lung squamous cell carcinoma based on the degree of tumor-infiltrating immune cells and molecular typing

Liquid chromatography coupled to high-resolution mass spectrometry metabolomics: A useful tool for investigating tumor secretome based on a three-dimensional co-culture model

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