bims-meluca 2021-07-11 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–07–11
six 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

Inhibition of AKT Enhances the Sensitivity of NSCLC Cells to Metformin.
The Effect of GLUT1 on Survival Rate and the Immune Cell Infiltration of Lung Adenocarcinoma and Squamous Cell Carcinoma: A Meta and Bioinformatics Analysis.
Additive Antiproliferative and Antiangiogenic Effects of Metformin and Pemetrexed in a Non-Small-Cell Lung Cancer Xenograft Model.
Association of the key genes in the pathophysiology between the Type 2 diabetes and Lung cancer.
Characterization of a ferroptosis and iron-metabolism related lncRNA signature in lung adenocarcinoma.
A feedback circuit comprising EHD1 and 14-3-3ζ sustains β-catenin/c-Myc-mediated aerobic glycolysis and proliferation in non-small cell lung cancer.

Anticancer Res. 2021 Jul;41(7): 3481-3487

Inhibition of AKT Enhances the Sensitivity of NSCLC Cells to Metformin.

Se-Kyeong Jang, Sung-Eun Hong, DA-Hee Lee, Ji Yea Kim, Ji-Young Kim, Jungil Hong, In-Chul Park, Hyeon-Ok Jin.

   BACKGROUND/AIM: Metformin is an antidiabetic drug that has been reported to have antitumor activity in many cancer types. This study investigated the molecular mechanisms underlying the antitumor effect of metformin.
MATERIALS AND METHODS: We investigated the molecular mechanism of the antitumor effect of metformin alone and in combination with AKT serine/threonine kinase (AKT) inhibition via cell viability and western blot analyses.
RESULTS: Notably, metformin increased the phosphorylation of AKT at serine 473 using protein array screening. Metformin-induced AKT activation was markedly suppressed by siRNA targeting activating transcription factor 4 (ATF4) but not AMP-activated protein kinase α. These results indicate that AKT activation by metformin was induced in an ATF4-dependent and AMPKα-independent manner. Treatment using metformin combined with MK-2206, an AKT inhibitor, or a siRNA for AKT markedly reduced the viability of cells compared with those cells treated with these agents alone. In addition, MK-2206 increased cell sensitivity to the combination of metformin with ionizing radiation or cisplatin.
CONCLUSION: Inhibition of AKT can enhance the antitumor effect of metformin and would be a promising strategy to sensitize non-small-cell lung cancer to a combination of metformin with radiation or cisplatin.

Keywords:  AKT; ATF4; cisplatin; ionizing radiation; metformin; non-small-cell lung cancer

DOI:  https://doi.org/10.21873/anticanres.15135
Anticancer Agents Med Chem. 2021 Jul 07.

The Effect of GLUT1 on Survival Rate and the Immune Cell Infiltration of Lung Adenocarcinoma and Squamous Cell Carcinoma: A Meta and Bioinformatics Analysis.

Guihua Zhang, Rong Dong, Demiao Kong, Bo Liu, Yan Zha, Meng Luo.

   BACKGROUND: Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are two major subtypes of non-small cell lung cancer (NSCLC). Studies have shown that abnormal expression of glucose transport type 1 (GLUT1) in NSCLC patients has been associated with progression, aggressiveness, and poor clinical outcome. However, the clinical effect of GLUT1 expression on LUAD and LUSC is unclear.
OBJECTIVE: This study aims to learn more about the character of GLUT1 in LUAD and LUSC.
METHODS: A meta-analysis was performed to evaluate the GLUT1 protein level, and bioinformatics analysis was used to detect the GLUT1 mRNA expression level, survival differences, and the infiltration abundance of immune cells in samples from TCGA. Meanwhile, functional and network analysis was conducted to detect important signaling pathways and key genes with the Gene Expression Omnibus (GEO) dataset.
RESULTS: Our results showed that GLUT1 was over-expressed both in LUAD and LUSC. LUAD patients with high GLUT1 expression had a poor prognosis. Additionally, GLUT1 was related to B cell and neutrophil infiltration of LUAD. In LUSC, GLUT1 was correlated with tumor purity, B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration. The GEO dataset analysis results suggested GLUT1 potentially participated in the p53 signaling pathway and metabolism of xenobiotics by cytochrome P450 and was associated with KDR, TOX3, AGR2, FOXA1, ERBB3, ANGPT1, and COL4A3 gene in LUAD and LUSC.
CONCLUSION: GLUT1 might be a potential biomarker for aggressive progression and poor prognosis in LUAD, and a therapeutic biomarker in LUSC.

Keywords:  glucose transport type 1; immune cell infiltration; lung adenocarcinoma; lung squamous cell carcinoma; non-small cell lung cancer; survival rate.

DOI:  https://doi.org/10.2174/1871520621666210708115406
Front Cell Dev Biol. 2021 ;9 688062

Additive Antiproliferative and Antiangiogenic Effects of Metformin and Pemetrexed in a Non-Small-Cell Lung Cancer Xenograft Model.

Jiun-Long Wang, Ying-Wei Lan, Yi-Ting Tsai, Ying-Cheng Chen, Theresa Staniczek, Yung-An Tsou, Chih-Ching Yen, Chuan-Mu Chen.

  Lung cancer is heterogeneous and challenging to cope with once it has progressed. Chemotherapy is the first step once no active driver mutation has been discovered. Non-antitumor drugs have been found to be beneficial when used as adjuvants to chemotherapy. In this study, the additive effect and mechanism of metformin combined with pemetrexed in non-small-cell lung cancer (NSCLC) cells were elucidated. Three NSCLC cell lines, A549, H1975, and HCC827, were used to analyze tumor cell proliferation, colony formation and the cell cycle in vitro when exposed to metformin alone, pemetrexed alone or their combination. We found that combination treatment in three cell lines exerted antiproliferative effects through cell cycle arrest in the S phase. An ex vivo chicken chorioallantoic membrane (CAM) assay was used to examine the antiangiogenic effect of metformin combined with pemetrexed on vascular structure formation. We further created an A549 orthotopic xenograft model with an in vivo imaging system (IVIS) and explored the associated indicators involved in the tumorigenic process. The in vitro results showed that the combination of metformin and pemetrexed exhibited an antiproliferative effect in reducing cell viability and colony formation, the downregulation of cyclin D1 and A2 and the upregulation of CDKN1B, which are involved in the G1/S phase. For antiangiogenic effects, the combination therapy inhibited the vascular structure, as proven by the CAM assay. We elucidated that combination therapy could target VEGFA and Endoglin by RT-qPCR, ELISA and histopathological findings in an A549 orthotopic NSCLC xenograft model. Our research demonstrated the additive antiproliferative and antiangiogenic effects of the combination of metformin with pemetrexed in NSCLC and could be applied to clinical lung cancer therapy.

Keywords:  angiogenesis; chorioallantoic membrane; lung cancer; metformin; orthotopic xenograft; pemetrexed

DOI:  https://doi.org/10.3389/fcell.2021.688062
Neuro Endocrinol Lett. 2021 May 04. 42(2): 63-69

Association of the key genes in the pathophysiology between the Type 2 diabetes and Lung cancer.

Tingting Tao, Jin Li, Tingting Hang, Peixin Duan.

BACKGROUND: Although several studies have demonstrated that preexisting diabetes mellitus (DM) may increase the risk of lung cancer (LC), rare research of the certain pathophysiology was reported up to now.
METHODS: Aiming to identify the differentially expressed genes (DEGs) between type 2 diabetes mellitus (T2DM) and LC, gene expression profiles GSE55650 and GSE136043 were downloaded in the Gene Expression Omnibus (GEO) database. We carried out biological function analysis to seek significantly enriched pathways and functions for DEGs. A protein-protein interaction (PPI) network was performed to explore hub genes for diabetes and LC during Metformin's treatment.
RESULTS: Finally, the study found that there were 756 genes overlapped between T2DM and LC samples. It contained 133 common genes up-regulated both in T2DM and LC (DEGs1), 275 independent genes down-regulated in LC (DEGs2), 246 common genes down-regulated in both (DEGs3), and 102 independent genes down-regulated in diabetes (DEGs4). Glycine, serine and threonine metabolism, arginine and proline metabolism, TGF-beta signaling pathway, and pathways in cancer were significantly enriched in DEGs2 and DEGs4. Four hub genes (C3, THBS1, CXCL1, and TTN) were identified after treatment of Metformin (P<0.05, T-test).
CONCLUSION: Our findings demonstrated that the above-mentioned hub genes might play functional roles in the treatment of metformin for patients with diabetes and LC.
Cancer Cell Int. 2021 Jul 03. 21(1): 340

Characterization of a ferroptosis and iron-metabolism related lncRNA signature in lung adenocarcinoma.

Jie Yao, Xiao Chen, Xiao Liu, Rui Li, Xijia Zhou, Yiqing Qu.

   BACKGROUND: Long non-coding RNAs (lncRNAs) are increasingly recognized as the crucial mediators in the regulation of ferroptosis and iron metabolism. A systematic understanding of ferroptosis and iron-metabolism related lncRNAs (FIRLs) in lung adenocarcinoma (LUAD) is essential for new diagnostic and therapeutic strategies.
METHODS: FIRLs were obtained through Pearson correlation analysis between ferroptosis and iron-metabolism related genes and all lncRNAs. Univariate and multivariate Cox regression analysis were used to identify optimal prognostic lncRNAs. Next, a novel signature was constructed and risk score of each patient was calculated. Survival analysis and ROC analysis were performed to evaluate the predictive performance using The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) and Gene Expression Omnibus (GEO) datasets, respectively. Furthermore, multivariate Cox and stratification analysis were used to assess prognostic value of this signature in whole cohort and various subgroups. The correlation of risk signature with immune infiltration and gene mutation was also discussed. The expression of lncRNAs was verified by quantitative real-time PCR (qRT-PCR).
RESULTS: A 7-FIRLs signature including ARHGEF26-AS1, LINC01137, C20orf197, MGC32805, TMPO-AS1, LINC00324, and LINC01116 was established in the present study to assess the overall survival (OS) of LUAD. The survival analysis and ROC curve indicated good predictive performance of the signature in both the TCGA training set and the GEO validation set. Multivariate Cox and stratification analysis indicated that the 7-FIRLs signature was an independent prognostic factor for OS. Nomogram exhibited robust validity in prognostic prediction. Differences in immune cells, immune functions and gene mutation were also found between high-risk and low-risk groups.
CONCLUSIONS: This risk signature based on the FIRLs may be promising for the clinical prediction of prognosis and immunotherapeutic responses in LUAD patients.

Keywords:  Ferroptosis; Immune infiltration; Iron metabolism; Lung adenocarcinoma; Signature; lncRNA

DOI:  https://doi.org/10.1186/s12935-021-02027-2
Cancer Lett. 2021 Jul 02. pii: S0304-3835(21)00308-6. [Epub ahead of print]520 12-25

A feedback circuit comprising EHD1 and 14-3-3ζ sustains β-catenin/c-Myc-mediated aerobic glycolysis and proliferation in non-small cell lung cancer.

Jian Huang, Fanglin Tian, Ying Song, Mengru Cao, Shi Yan, Xiuwen Lan, Yimeng Cui, Yaowen Cui, Yue Cui, Dexin Jia, Li Cai, Ying Xing, Xin Wang.

  Mammalian Eps15 homology domain 1 (EHD1) participates in the development of non-small cell lung cancer (NSCLC). However, its role in mediating aerobic glycolysis remains unclear. Herein, microarray analysis revealed that EHD1 expression was significantly correlated with the glycolysis/gluconeogenesis pathway. Clinically, EHD1 expression was positively correlated with the maximum standard uptake value (SUVmax) in 18F-FDG PET/CT scans. Additionally, EHD1 knockdown inhibited aerobic glycolysis and proliferation in vitro and in vivo. Furthermore, Wnt/β-catenin signaling was identified as a critical EHD1-regulated pathway. Co-IP, native gel electrophoresis, and immunoblotting showed that EHD1 contributed to 14-3-3 dimerization via 14-3-3ζ and subsequent activation of β-catenin/c-Myc signaling. Analysis of the EHD1 regulatory region via ENCODE revealed the potential for c-Myc recruitment, leading to transcriptional activation of EHD1 and formation of an EHD1/14-3-3ζ/β-catenin/c-Myc positive feedback circuit. Notably, blocking this circuit with a Wnt/β-catenin inhibitor dramatically inhibited tumor growth in vivo. The positive correlations among EHD1, 14-3-3ζ, c-Myc, and LDHA were further confirmed in NSCLC tissues. Collectively, our study demonstrated that EHD1 activates a 14-3-3ζ/β-catenin/c-Myc regulatory circuit that synergistically promotes aerobic glycolysis and may constitute a promising therapeutic target for NSCLC.

Keywords:  EHD1; Metabolic reprogramming; Positive feedback loop; Tumor proliferation

DOI:  https://doi.org/10.1016/j.canlet.2021.06.023