bims-meluca 2022-01-09 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–01–09
nine 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

Chromatin remodeling induced by ARID1A loss in lung cancer promotes glycolysis and confers JQ1 vulnerability.
Succinate dehydrogenase 5 regulates lung cancer metastasis by reprogramming glucose metabolism.
Heterogeneity of glutamine metabolism in acquired-EGFR-TKI-resistant lung cancer.
Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4.
A Supramolecular Nanoparticle of Pemetrexed Improves the Anti-Tumor Effect by Inhibiting Mitochondrial Energy Metabolism.
Identification of a Six-Gene SLC Family Signature With Prognostic Value in Patients With Lung Adenocarcinoma.
Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis.
Immunohistochemical expression of VEGFR1 in non small cell lung carcinomas: Lower VEGFR1 expression is asociated with squamous cell carcinoma subtype and high SUV max values in 18F-FDG PET.
METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification.

Cancer Res. 2022 Jan 05. pii: canres.0763.2021. [Epub ahead of print]

Chromatin remodeling induced by ARID1A loss in lung cancer promotes glycolysis and confers JQ1 vulnerability.

Xiaoyu Liu, Zhi Li, Zhongmin Wang, Fei Liu, Linling Zhang, Jingjing Ke, Xu Xu, Yuefang Zhang, Yiting Yuan, Tao Wei, Qungang Shan, Yingjie Chen, Wei Huang, Jie Gao, Nan Wu, Fuliang Chen, Lunquan Sun, Zilong Qiu, Yuezhen Deng, Wang Xiaojing.

ARID1A is a key mammalian SWI/SNF complex subunit that is mutated in 5%-11% of lung cancers. Although recent studies have elucidated the mechanism underlying dysregulation of SWI/SNF complexes in cancers, the significance of ARID1A loss and its implications in lung cancers remain poorly defined. This study investigates how ARID1A loss affects initiation and progression of lung cancer. In genetically engineered mouse models bearing mutant Kras and a deficient Trp53 allele (KP), ARID1A loss (KPA) promoted lung tumorigenesis. Analysis of the transcriptome profiles of KP and KPA tumors suggested enhanced glycolysis following ARID1A loss, and expression of the glycolytic regulators Pgam1, Pkm, and Pgk1 was significantly increased in ARID1A-deficient lung tumors. Furthermore, ARID1A loss increased chromatin accessibility and enhanced HIF1α binding to the promoter regions of Pgam1, Pkm, and Pgk1. Loss of ARID1A in lung adenocarcinoma also resulted in loss of histone deacetylase 1 (HDAC1) recruitment, increasing acetylation of histone 4 lysine at the promoters of Pgam1, Pkm, and Pgk1 and subsequently enhancing BRD4-driven transcription of these genes. Metabolic analyses confirmed that glycolysis is enhanced in ARID1A-deficient tumors, and genetic or pharmacologic inhibition of glycolysis inhibited lung tumorigenesis in KPA mice. Treatment with the small molecule bromodomain and extra terminal protein (BET) inhibitor JQ1 compromised both initiation and progression of ARID1A-deficient lung adenocarcinoma. ARID1A negatively correlated with glycolysis-related genes in human lung adenocarcinoma. Overall, ARID1A loss leads to metabolic reprogramming that supports tumorigenesis but also confers a therapeutic vulnerability that could be harnessed to improve the treatment of ARID1A-deficient lung cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0763
J Thorac Dis. 2021 Nov;13(11): 6427-6438

Succinate dehydrogenase 5 regulates lung cancer metastasis by reprogramming glucose metabolism.

Jie Li, Zhan Tuo, Yan Zong, Jun Liu.

   Background: Lung cancer is the leading cause of cancer-related death globally, with many of these patients also suffering from diabetes. Previous studies have shown that diabetes may contribute to cancer progression through hyperglycemia. However, the underlying mechanism remains largely unknown. This study aimed to investigate the role of succinate dehydrogenase 5 (SDH5), an enzyme required for assembling respiratory complex II in lung cancer patients with diabetes.
Methods: The expression levels of SDH5 in patient plasma and tissue were determined by RT-qPCR. Western blotting, immunofluorescence (IF), and immunohistology (IHC) were used to examine protein expression. Migration and invasion assays were performed using Transwell assays. Reactive oxygen species (ROS) production was detected by flow cytometry. Bioluminescent imaging (BLI) was used to detect tumor metastasis in a lung orthotopic mouse model.
Results: In samples from non-small cell lung cancer (NSCLC) patients with diabetes, SDH5 mRNA levels were significantly lower in both plasma and tissue among later stage patients. TCGA data showed that low SDH5 expression was correlated with a higher expression of genes involved in glycolysis and metastasis. In vitro, high glucose conditions alone induced epithelial-to-mesenchymal transition (EMT) in cells, an effect that was further reinforced by SDH5 depletion. Additionally, depleting SDH5 promoted glucose consumption and lactate production. The underlying mechanism indicates that depleting SDH5 stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), which is dependent on ROS production. In vivo, SDH5-deficient tumor-bearing mice had multiple organ metastases, which is consistent with the in vitro findings.
Conclusions: Our findings suggest that SDH5 deficiency activates HIF-1α to promote EMT under high glucose conditions and represents a predictive marker for NSCLC patients with diabetes.

Keywords:  Non-small cell lung cancer (NSCLC); epithelial-to-mesenchymal transition (EMT); high glucose; hypoxia-inducible factor 1-alpha (HIF-1α); succinate dehydrogenase 5 (SDH5)

DOI:  https://doi.org/10.21037/jtd-21-1769
Life Sci. 2022 Jan 03. pii: S0024-3205(21)01261-3. [Epub ahead of print] 120274

Heterogeneity of glutamine metabolism in acquired-EGFR-TKI-resistant lung cancer.

Suntae Kim, Jang Su Jeon, Yong June Choi, Ga Hee Baek, Sang Kyum Kim, Keon Wook Kang.

   AIMS: The purpose of this study was to evaluate the heterogeneities of glutamine metabolism in EGFR-TKI-resistant lung cancer cells and its potential as a therapeutic target.
MAIN METHODS: Cell proliferation and cell cycle assays was performed by IncuCyte real-time analysis and flow cytometry, respectively. Tumor growth was assessed in xenografts implanted with HCC827 GR. An isotopologue analysis was conducted by LC-MS/MS using 13C-(U)-glutamine labeling to determine the amounts of metabolites. Cellular ATP and mitochondrial oxidative phosphorylation were determined by XFp analysis.
KEY FINDINGS: We found that the cell growth of the two acquired EGFR-TKI-resistant lung cancer cells lines (HCC827 GR and H292 ER) depends on glutamine. In HCC827 GR, glutamine deficiency caused reduced GSH synthesis and, subsequently, enhanced ROS generation relative to their parental cells, HCC827. On the other hand, in H292 ER, glutamine mainly acted as a carbon source for TCA-cycle intermediates, and its depletion led to reduced mitochondrial ATP production. CB-839, a specific GLS inhibitor, inhibited the latter's conversion of glutamine to glutamate and exerted enhanced anti-proliferating effects on the two acquired EGFR-TKI-resistant lung cancer cell lines versus their parental cell lines. Moreover, oral administration of CB-839 significantly suppressed HCC827 GR tumor growth in the xenograft model.
SIGNIFICANCE: These findings suggest that glutamine dependency in acquired EGFR-TKI-resistant lung cancer is heterogeneous and that inhibition of glutamine metabolism by CB-839 may serve as a therapeutic tool for acquired EGFR-TKI-resistant lung cancer.

Keywords:  Acquired EGFR-TKI-resistant lung cancer; CB-839; CB-839 (Telaglenastat; Glutamine metabolism; PubChem CID: 71577426)

DOI:  https://doi.org/10.1016/j.lfs.2021.120274
Open Med (Wars). 2022 ;17(1): 87-95

Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4.

Luming Jin, Chaoyang Chen, Lipeng Huang, Qingyu Sun, Liang Bu.

  Long noncoding RNA (lncRNA), specifically the upregulation of lncRNA NR2F1 antisense RNA 1 (NR2F1-AS1), has been involved in the progression of non-small cell lung cancer (NSCLC), but the mechanisms that underlie this remain unclear. In this study, the expression of NR2F1-AS1, miR-363-3p, and SOX4 was assessed in NSCLC cells. A loss-of-function assay was used to measure the tumorigenicity of NSCLC cells. The glycolysis and glutamine metabolism of NSCLC cells was also measured via extracellular acidification rate, consumption of glucose and glutamine, and production of lactate and ATP. The relationships among NR2F1-AS1, miR-363-3p, and SOX4 were detected via dual-luciferase reporter assay. HK-2, GLS1, and SOX4 levels were also analyzed. We found that both NSCLC tissues and cells had higher levels of NR2F1-AS1. Silencing of NR2F1-AS1 inhibited the tumorigenicity of cells in vitro and reduced the glycolysis and glutamine metabolism of NSCLC cells. Regarding its mechanism, NR2F1-AS1 positively regulated the SOX4 level by sponging miR-363-3p. Furthermore, miR-363-3p inhibition or SOX4 overexpression reversed the repressing role of sh-NR2F1-AS1 in the tumorigenicity of NSCLC cells. In summary, NR2F1-AS1 promotes the tumorigenicity of NSCLC cells by regulating miR-363-3p/SOX4.

Keywords:  NR2F1-AS1; SOX4; glycolysis; miR-363-3p; non-small cell lung cancer

DOI:  https://doi.org/10.1515/med-2021-0403
Front Bioeng Biotechnol. 2021 ;9 804747

A Supramolecular Nanoparticle of Pemetrexed Improves the Anti-Tumor Effect by Inhibiting Mitochondrial Energy Metabolism.

Hui Liu, Chunlei Guo, Yuhong Shang, Lin Zeng, Haixue Jia, Zhongyan Wang.

  In recent years, supramolecular nanoparticles consisting of peptides and drugs have been regarded as useful drug delivery systems for tumor therapy. Pemetrexed (PEM) is a multitarget drug that is effective for many cancers, such as non-small cell lung cancer. Here, RGD-conjugated molecular nanoparticles mainly composed of an anticancer drug of PEM (PEM-FFRGD) were prepared to deliver PEM to tumors. The peptide could self-assemble into a nanoparticle structure with diameter of about 20 nm. Moreover, the nanoparticle showed favorable solubility and biocompatibility compared with those of PEM, and the MTT test on A549 and LLC cells showed that the PEM-FFRGD nanoparticles had stronger cytotoxic activity than PEM alone. Most importantly, the nanoparticle could promote tumor apoptosis and decrease mitochondrial energy metabolism in tumors. In vivo studies indicated that PEM-FFRGD nanoparticles had enhanced antitumor efficacy in LLC tumor-bearing mice compared to that of PEM. Our observations suggested that PEM-FFRGD nanoparticles have great practical potential for application in lung cancer therapy.

Keywords:  metabolism; mitochondrial; pemetrexed; supramolecular nanoparticle; tumor therapy

DOI:  https://doi.org/10.3389/fbioe.2021.804747
Front Cell Dev Biol. 2021 ;9 803198

Identification of a Six-Gene SLC Family Signature With Prognostic Value in Patients With Lung Adenocarcinoma.

Jing Zhu, Yong Mou, Shenglan Ye, Hongling Hu, Rujuan Wang, Qing Yang, Yi Hu.

  Given the importance of solute carrier (SLC) proteins in maintaining cellular metabolic homeostasis and that their dysregulation contributes to cancer progression, here we constructed a robust SLC family signature for lung adenocarcinoma (LUAD) patient stratification. Transcriptomic profiles and relevant clinical information of LUAD patients were downloaded from the TCGA and GEO databases. SLC family genes differentially expressed between LUAD tissues and adjacent normal tissues were identified using limma in R. Of these, prognosis-related SLC family genes were further screened out and used to construct a novel SLC family-based signature in the training cohort. The accuracy of the prognostic signature was assessed in the testing cohort, the entire cohort, and the external GSE72094 cohort. Correlations between the prognostic signature and the tumor immune microenvironment and immune cell infiltrates were further explored. We found that seventy percent of SLC family genes (279/397) were differentially expressed between LUAC tissues and adjacent normal. Twenty-six genes with p-values < 0.05 in univariate Cox regression analysis and Kaplan-Meier survival analysis were regarded as prognosis-related SLC family genes, six of which were used to construct a prognostic signature for patient classification into high- and low-risk groups. Kaplan-Meier survival analysis in all internal and external cohorts revealed a better overall survival for patients in the low-risk group than those in the high-risk group. Univariate and multivariate Cox regression analyses indicated that the derived risk score was an independent prognostic factor for LUAD patients. Moreover, a nomogram based on the six-gene signature and clinicopathological factors was developed for clinical application. High-risk patients had lower stromal, immune, and ESTIMATE scores and higher tumor purities than those in the low-risk group. The proportions of infiltrating naive CD4 T cells, activated memory CD4 T cells, M0 macrophages, resting dendritic cells, resting mast cells, activated mast cells, and eosinophils were significantly different between the high- and low-risk prognostic groups. In all, the six-gene SLC family signature is of satisfactory accuracy and generalizability for predicting overall survival in patients with LUAD. Furthermore, this prognostics signature is related to tumor immune status and distinct immune cell infiltrates in the tumor microenvironment.

Keywords:  immune microenvironment; lung adenocarcinoma; prognosis; signature; solute carrier

DOI:  https://doi.org/10.3389/fcell.2021.803198
Cancer Cell Int. 2022 Jan 07. 22(1): 13

Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis.

Peng Xu, Kang Hu, Ping Zhang, Zhi-Gang Sun, Nan Zhang.

   BACKGROUND: N6-methyladenosine (m6A) is a dynamic and reversible internal RNA structure of eukaryotic mRNA. YTH domain family 2 (YTHDF2), an m6A-specific reader YTH domain family, plays fundamental roles in several types of cancer. However, the function of YTHDF2 in lung squamous cell carcinoma (LUSC) remains elusive.
METHODS: The knockdown and overexpression of YTHDF2 in LUSC cells were conducted to detect the biological characteristics of YTHDF2. In vivo assays, the role of YTHDF2 in tumor growth was further uncovered. In vitro assays, YTHDF2 was confirmed to be involved in activating the mTOR/AKT signaling and YTHDF2 overexpression induced the EMT process in LUSC. Clinically, immunohistochemical staining revealed the relationship between YTHDF2 expression levels and the clinicopathological characteristics of lung squamous cell carcinoma patients. Moreover, quantitative PCR (qPCR), western blot, CCK8 assay, transwell assay, and wound-healing assay were used to detect the expression level and function of YTHDF2 under hypoxia exposure in LUSC cells.
RESULTS: The results showed that hypoxia-mediated YTHDF2 overexpression promotes cell proliferation and invasion by activating the mTOR/AKT axis, and YTHDF2 overexpression induces the EMT process in LUSC. Moreover, YTHDF2 is closely associated with pN (pN- 37.0%, pN + 73.9%; P = 0.002) and pTNM stage (pI 50.0%, PII 43.3%, pIIIa 80.6%; P = 0.007), ultimately resulting in poor survival for LUSC patients.
CONCLUSION: In brief, the results highlight high-YTHDF2 expression predicted a worse prognosis of LUSC, while hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT signaling pathway.

Keywords:  EMT; Hypoxia; LUSC; METTL14; YTHDF2; mTOR/AKT

DOI:  https://doi.org/10.1186/s12935-021-02368-y
Rev Esp Med Nucl Imagen Mol (Engl Ed). 2022 Jan-Feb;41(1):pii: S2253-8089(21)00001-X. [Epub ahead of print]41(1): 28-31

Immunohistochemical expression of VEGFR1 in non small cell lung carcinomas: Lower VEGFR1 expression is asociated with squamous cell carcinoma subtype and high SUV max values in 18F-FDG PET.

M C Pombo Pasín, V Pubul Nuñez, L García Bernardo, F Gude Sampedro, I Abdulkader-Nallib, A Ruibal Morell.

   BACKGROUND: To study the possible relation between immunohistochemical expression of vascular endothelial growth factor receptor 1 (VEGFR1) and the maximum standardised uptake value (SUV max) of 18F-FDG PET in patients with non small cell lung cancer (NSCLC).
MATERIAL AND METHODS: The study included 39 patients with NSCLC (24 squamous cell carcinomas and 15 adenocarcinomas). According to the clinical stage, the patients were distributed as follows: 8 stage I, 7 stage II, 15 stage III and 9 stage IV. Immunohistochemical expression of VEGFR1 was studied through the technique of tissue-matrix using Tissue Arrayer Device (Beecher Instruments, Sun Prairie, WI), using the polyclonal antibody against VEGFR1 (Santa Cruz Biotechnology, California, USA).
RESULTS: Positive VEGFR1 immunohistochemical expression was noted in 23 cases (59%). The number of positive tumours was not related with clinical stage but there was a different statistically significant association (p:0,0009) between VEGFR1 positivity and histological type, corresponding the greater percentages of positive results to adenocarcinomas (93,3%) versus in squamous cell carcinomas (37,5%). Likewise, SUV max values were higher (p: 0,039) in negative VEGFR1 carcinomas than in positive VEGFR1 tumors (r: 4-32,1; 16,4+/-6,4 (median 16,1) vs r: 3-47; 14,5+/-8,6 (12,8)).
CONCLUSIONS: Our results led us to consider that in NSCLC, the negative VEGFR1 immunohistochemical expression is associated significantly with squamous cell carcinomas subtype and with higher SUV max values in 18F-FDG-PET.

Keywords:  SUV max-(18)F-FDG-PET; SUV max-18F-FDG-PET; VEGFR1; carcinomas de células no pequeñas; non-small cell carcinomas

DOI:  https://doi.org/10.1016/j.remnie.2021.01.001
Cancer Cell Int. 2022 Jan 07. 22(1): 11

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification.

Yiming Xu, Dandan Lv, Chao Yan, Hua Su, Xue Zhang, Yangfeng Shi, Kejing Ying.

   BACKGROUND: N6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression.
METHODS: The expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD.
RESULTS: The results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc-, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues.
CONCLUSIONS: These findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.

Keywords:  Ferroptosis; Lung adenocarcinoma; METTL3; N6-methyladenosine (m6a) modification; SLC7A11

DOI:  https://doi.org/10.1186/s12935-021-02433-6