bims-meluca 2022-04-03 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–04–03
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Concise Review: Gene of The Month KEAP1-mutant non-small cell lung cancer: the catastrophic failure of a cell-protecting hub.
An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer.
Multi-Omics Signatures Identification for LUAD Prognosis Prediction Model Based on the Integrative Analysis of Immune and Hypoxia Signals.
The Effect of Extracellular Superoxide Dismutase (SOD3) Gene in Lung Cancer.
Sinapine induced ferroptosis in non-small cell lung cancer cells by upregulating transferrin/transferrin receptor and downregulating SLC7A11.
TRIM46 activates AKT/HK2 signaling by modifying PHLPP2 ubiquitylation to promote glycolysis and chemoresistance of lung cancer cells.
Increased PPARD Expression May Play a Protective Role in Human Lung Adenocarcinoma and Squamous Cell Carcinoma.
H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.

J Thorac Oncol. 2022 Mar 26. pii: S1556-0864(22)00166-6. [Epub ahead of print]

Concise Review: Gene of The Month KEAP1-mutant non-small cell lung cancer: the catastrophic failure of a cell-protecting hub.

Stefano Scalera, Marco Mazzotta, Clelia Cortile, Eriseld Krasniqi, Ruggero De Maria, Federico Cappuzzo, Gennaro Ciliberto, Marcello Maugeri-Saccà.

Mutations in the KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (Nuclear factor erythroid 2-related factor 2) pathway are common in non-small cell lung cancer (NSCLC), albeit with a prevalence of KEAP1 mutations in lung adenocarcinoma (LUAD) and an equal representation of KEAP1 and NFE2L2 (the gene encoding for NRF2) alterations in lung squamous cell carcinoma (LUSC). The KEAP1-NRF2 axis is a crucial modulator of cellular homeostasis, enabling cells to tolerate oxidative and metabolic stresses, as well as xenobiotics. The complex cytoprotective response orchestrated by NRF2-mediated gene transcription embraces detoxification mechanisms, ferroptosis protection and metabolic reprogramming. Given that the KEAP1-NRF2 pathway controls core cellular functions, it is not surprising that a number of clinical studies connected KEAP1 mutations to increased resistance to chemotherapy, radiotherapy and targeted agents. More recently, an immune-cold tumor microenvironment was described as a typical feature of KEAP1-mutant LUAD. Consistently, a reduced efficacy of immunotherapy was reported in the KEAP1-mutant background. However, the connection between KEAP1 and immune-resistance seems more complex and dependent on coexisting genomic alterations. Given the clinical implications of deregulated KEAP1-NRF2 pathway in lung cancer, the development of pathway-directed anticancer treatments should be considered a priority in the domain of thoracic oncology.

DOI: https://doi.org/10.1016/j.jtho.2022.03.011
Cell Commun Signal. 2022 Mar 28. 20(1): 40

An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer.

Rui Zhang, Guo-Jun Geng, Jian-Guang Guo, Yan-Jun Mi, Xiao-Lei Zhu, Ning Li, Hong-Ming Liu, Jun-Feng Lin, Jian-Weng Wang, Guang Zhao, Guan-Zhi Ye, Bo-An Li, Qi-Cong Luo, Jie Jiang.

   BACKGROUND: Tumor cells tend to utilize glycolysis rather than aerobic respiration even under aerobic conditions. OVOL2, an inhibitory C2H2 zinc finger transcription factor, is a potential tumor suppressor in cancers. However, the association between OVOL2 and tumor energy metabolism is unknown.
METHODS: Western blotting was used to determine the expression of OVOL2 in different non-small cell lung cancer (NSCLC) cell lines and mouse models. The metabolic parameters in NSCLC cells following overexpression or knockdown OVOL2 were examined. To define the mechanism by which OVOL2 regulates aerobic glycolysis, interacting protein of OVOl2 and downstream molecular events were identified by luciferase assay and co-immunoprecipitation. We documented the regulatory mechanism in mouse xenograft models. Finally, clinical relevance of OVOL2, NF-κB signaling and GLUT1 was measured by immunostaining.
RESULTS: OVOL2 is downregulated in NSCLC and overexpression of OVOL2 inhibits the survival of cancer cells. Moreover, OVOL2 directly binds to P65 and inhibits the recruitment of P300 but facilitates the binding of HDAC1 to P65, which in turn negatively regulates NF-κB signaling to suppress GLUT1 translocation and glucose import. In contrast, OVOL2 expression is negatively regulated by NF-κB signaling in NSCLC cells via the ubiquitin-proteasome pathway. Re-expression of OVOL2 significantly compromise NF-κB signaling-induced GLUT1 translocation, aerobic glycolysis in NSCLC cells and mouse models. Immunostaining revealed inverse correlations between the OVOL2 and phosphorylated P65 levels and between the OVOL2 and membrane GLUT1 levels, and a strong correlation between the phosphorylated P65 and membrane GLUT1 levels.
CONCLUSIONS: These results suggest a regulatory circuit linking NF-κB and OVOL2, which highlights the role of NF-κB signaling and OVOL2 in the modulation of glucose metabolism in NSCLC. Video Abstract.

Keywords:  Glucose import; NF-κB signaling; NSCLC; OVOL2

DOI:  https://doi.org/10.1186/s12964-022-00845-z
Front Cell Dev Biol. 2022 ;10 840466

Multi-Omics Signatures Identification for LUAD Prognosis Prediction Model Based on the Integrative Analysis of Immune and Hypoxia Signals.

Yuqing Lou, Qin Shi, Yanwei Zhang, Ying Qi, Wei Zhang, Huimin Wang, Jun Lu, Baohui Han, Hua Zhong.

  Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer with heterogeneous outcomes and diverse therapeutic responses. However, the understanding of the potential mechanism behind LUAD initiation and progression remains limited. Increasing evidence shows the clinical significance of the interaction between immune and hypoxia in tumor microenvironment. To mine reliable prognostic signatures related to both immune and hypoxia and provide a more comprehensive landscape of the hypoxia-immune genome map, we investigated the hypoxia-immune-related alteration at the multi-omics level (gene expression, somatic mutation, and DNA methylation). Multiple strategies including lasso regression and multivariate Cox proportional hazards regression were used to screen the signatures with clinical significance and establish an incorporated prognosis prediction model with robust discriminative power on survival status on both the training and test datasets. Finally, combing all the samples, we constructed a robust model comprising 19 signatures for the prognosis prediction of LUAD patients. The results of our study provide a comprehensive landscape of hypoxia-immune related genetic alterations and provide a robust prognosis predictor for LUAD patients.

Keywords:  hypoxia; immune; lung adenocarcinoma; multi-omics biomarker; prognosis prediction

DOI:  https://doi.org/10.3389/fcell.2022.840466
Front Oncol. 2022 ;12 722646

The Effect of Extracellular Superoxide Dismutase (SOD3) Gene in Lung Cancer.

Yundi Zhang, Xuan Lu, Yueyang Zhang, Dongbo Zhao, Haoming Gong, Yuxin Du, Hua Sun.

   Background: The recognition of new diagnostic and prognostic biological markers for lung cancer, the most severe malignant tumor, is an essential and eager study. In a microenvironment, superoxide dismutase 3 (SOD3) can adjust active oxygen, and it refers to a secreted antioxidant enzyme. It was also found to be cancer-related, and in lung cancer, it was remarkably down-regulated. More and more new cancer research focuses on the function of SOD3. Despite this, there is no good description of SOD3 function in the LC progression.
Methods: Through bioinformatics analysis, we found that SOD3 was a possible novel lung cancer gene in this study. We analyzed data sets from Gene Expression Comprehensive Database (GEO) and the Cancer Genome Atlas (TCGA), and SOD3 expression was studied in lung cancer. This study estimated the SOD3 diagnosis and prognosis through gene expression differential display, gene set enrichment analysis (GSEA), enrichment and genomes (KEGG) analysis, and gene ontology (GO). Then in order to investigate the SOD3 presentation in lung cancer cells, we used Western Blot and also applied Flow cytometry to detect the impact of anti-tumor medicine on tumor cell apoptosis.
Results: We found that the expression level of SOD3 in lung cancer was low (P = 4.218E-29), while the survival of lung cancer patients with high SOD3 expression was shorter (LUSC p =0.00086, LUAD p=0.00038). According to the result of western blot, the expression of SOD3 in tumor cells was higher than that in normal cells. The ratio of early apoptosis induced by anti-cancer drugs was 10.5% in normal cells, 35.1% in squamous cell carcinoma and 36.9% in adenocarcinoma.The SOD3 high expression was associated with poor survival probability by multivariate analysis (HR: 1.006, 95% CI 1.002-1.011, p=0.006). Moreover, SOD3 high expression group had higher ESTIMATE scores, and larger amount of immune infiltrating cells. SOD3 expression is correlated with PDCD1 and CTLA4 expression.
Conclusions: SOD3 gene can be used as a prognostic gene in lung cancer patients, and lung cancer patients with high expression of this gene can reap worse prognostic outcome. It can be used as a new clinical method and prognosticator for lung cancer patients.

Keywords:  SOD3; bioinformatic analysis; lung adenocarcinoma; lung cancer; lung squamous cancer

DOI:  https://doi.org/10.3389/fonc.2022.722646
Gene. 2022 Mar 28. pii: S0378-1119(22)00279-7. [Epub ahead of print] 146460

Sinapine induced ferroptosis in non-small cell lung cancer cells by upregulating transferrin/transferrin receptor and downregulating SLC7A11.

Min Shao, Qi Jiang, Chao Shen, Zhong Liu, Lihong Qiu.

  Sinapine (SI) is a naturally occurring product with biological properties, but its activity against non-small cell lung cancer (NSCLC) remains unclear. This research examined the anti-tumour effects of SI in NSCLC cells and the underlying mechanisms of any effects. SI induced ferroptosis, a novel form of cell death, by increasing intracellular ferrous iron, lipid peroxidation, and reactive oxygen species (ROS) in NSCLC cells. SI treatment resulted in transferrin and transferrin receptor upregulation, and inhibition of transferrin or the transferrin receptor reduced the ferroptosis caused by SI. SI treatment also resulted in a p-53 dependent downregulation of SLC7A11. Finally, we evaluated the effects of SI in vivo and it was found that SI also successfully inhibited the growth of NSCLC in vivo. In summary, our data demonstrated that SI triggered ferroptosis in NSCLC cells and may be a promising therapeutic agent for this condition.

Keywords:  ferroptosis; non-small cell lung cancer; p53; sinapine

DOI:  https://doi.org/10.1016/j.gene.2022.146460
Cell Death Dis. 2022 Mar 30. 13(3): 285

TRIM46 activates AKT/HK2 signaling by modifying PHLPP2 ubiquitylation to promote glycolysis and chemoresistance of lung cancer cells.

Jicheng Tantai, Xufeng Pan, Yong Chen, Yuzhou Shen, Chunyu Ji.

The incidence of lung cancer is increasing worldwide. Although great progress in lung cancer treatment has been made, the clinical outcome is still unsatisfactory. Tripartite motif (TRIM)-containing proteins has been shown to be closely related to tumor progression. However, the function of TRIM46 in lung cancer is largely unknown. Here, TRIM46 amplification was found in lung adenocarcinoma (LUAD) tissues and TRIM46 amplification was significantly associated with a poor survival rate. Overexpression of wild type TRIM46 increased the proliferation of LUAD cells and glycolysis, promoted xenografts growth, and enhanced cisplatin (DDP) resistance of LUAD cells via increased ubiquitination of pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) and upregulation of p-AKT. In contrast, overexpression of RING-mutant TRIM46 did not show any effects, suggesting the function of TRIM46 was dependent on the E3 ligase activity. Furthermore, we found that TRIM46 promoted LUAD cell proliferation and DDP resistance by enhancing glycolysis. PHLPP2 overexpression reversed the effects of TRIM46 overexpression. Amplification of TRIM46 also promoted LUAD growth and enhanced its DDP resistance in a patient-derived xenograft (PDX) model. In conclusion, our data highlight the importance of TRIM46/PHLPP2/AKT signaling in lung cancer and provide new insights into therapeutic strategies for lung cancer.

DOI: https://doi.org/10.1038/s41419-022-04727-7
PPAR Res. 2022 ;2022 9414524

Increased PPARD Expression May Play a Protective Role in Human Lung Adenocarcinoma and Squamous Cell Carcinoma.

Yong Zhu, Yedong Mi, Zhonghua Qin, Xuewei Jiang, Yibo Shan, Kamil Kural, Guiping Yu.

Peroxisome proliferator-activated receptor-δ, encoded by gene PPARD, is overexpressed in a majority of human lung cancer subtypes, but its role in the tumor progression remains poorly understood. We have analyzed the expression of PPARD in lung adenocarcinoma (LA) and squamous cell carcinoma (LSCC) datasets. The potential roles of PPARD in the pathological development of LA and LSCC were explored through literature-based pathway analysis and pathway enrichment analysis. In all LA datasets (N = 11) and in seven out of nine LSCC studies, the levels of PPARD were increased as compared to control tissues (log-fold changes were 0.37 ± 0.20 and 0.10 ± 0.37 for LA and LSCC, respectively). On average, the expression levels of PPARD in LA were higher than those in LSCC (p = 0.036). Pathway analysis showed that the overexpression of PPARD might play both positive and negative roles in the development of both LA and LSCC. Specifically, PPARD inhibits seven LSCC promoters and seven LA promoters and activates one LSCC inhibitor and another LA inhibitor. However, PPARD also activates six and one promoters of LA and LSCC, respectively, which would facilitate the development of LA/LSCC. Our results suggested a mixed role of PPARD in LA/LSCC, which may add new insights into the understanding of the PPARD-lung cancer relationship.

DOI: https://doi.org/10.1155/2022/9414524
Oncogene. 2022 Mar 30.

H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.

Chunwan Lu, Dafeng Yang, John D Klement, Yolonda L Colson, Nicholas H Oberlies, Cedric J Pearce, Aaron H Colby, Mark W Grinstaff, Zhuoqi Liu, Huidong Shi, Han-Fei Ding, Kebin Liu.

The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated with increased tumor cell apoptosis. Inhibition of aerobic glycolysis enzyme LDHA and G6PD had no significant effects on tumor cell survival. Ablation of G6PD had no significant effect on human mesothelioma and colon carcinoma xenograft growth in athymic mice. However, activation of G6PD with the G6PD-selective activator AG1 induced tumor cell death. AG1 increased tumor cell ROS production and the resultant extrinsic and intrinsic death pathways, mitochondrial processes, and unfolded protein response in tumor cells. Consistent with increased tumor cell death in vitro, AG1 suppressed human mesothelioma xenograft growth in a dose-dependent manner in vivo. Furthermore, AG1 treatment significantly increased tumor-bearing mouse survival in an intra-peritoneum xenograft athymic mouse model. Therefore, in human mesothelioma and colon carcinoma, G6PD is not essential for tumor growth. G6PD acts as a metabolic checkpoint to control metabolic flux towards the PPP to promote tumor cell apoptosis, and its expression is repressed by its promotor H3K9me3 deposition.

DOI: https://doi.org/10.1038/s41388-022-02283-0