bims-meluca 2020-05-24 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2020–05–24
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

CircLARP4 Suppresses Cell Proliferation, Invasion and Glycolysis and Promotes Apoptosis in Non-Small Cell Lung Cancer by Targeting miR-135b.
Hypoxia-induced GBE1 expression promotes tumor progression through metabolic reprogramming in lung adenocarcinoma.
IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway.
Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy.
Glycine metabolomic changes induced by anticancer agents in A549 cells.
Evaluation of nutritional status in non-small-cell lung cancer: screening, assessment and correlation with treatment outcome.

Onco Targets Ther. 2020 ;13 3717-3728

CircLARP4 Suppresses Cell Proliferation, Invasion and Glycolysis and Promotes Apoptosis in Non-Small Cell Lung Cancer by Targeting miR-135b.

Huawei Lu, Qingwei Guo, Guozhang Mao, Junwei Zhu, Fei Li.

   Background: CircLARP4 is reported to act as a tumor suppressor in some cancers. However, the detailed roles and molecular basis of circLARP4 in non-small cell lung cancer (NSCLC) tumorigenesis are still unclear. The aim of the study is to explore the potential roles and molecular basis of circLARP4 in NSCLC tumorigenesis.
Materials and Methods: qRT-PCR was taken to detect circLARP4 and miR-135b expressions. MTT assay, transwell invasion assay and flow cytometry analysis were applied to evaluate cell proliferation, invasion and apoptosis, respectively. Glycolysis was assessed by measuring hexokinase2 (HK2) expression, glucose consumption and lactate production. Association between circLARP4 and miR-135a was examined by luciferase reporter and RIP assays. The changes of the phosphatase and tension homolog (PTEN)/protein kinase B (AKT)/hypoxia-inducible factor-1α (HIF-1α) pathway were evaluated by Western blot. The nude mouse xenograft models were applied to verify the regulation of circLARP4 in vivo.
Results: CircLARP4 was decreased in NSCLC tissues and cells. CircLARP4 overexpression blocked cell proliferation and invasion, and facilitated apoptosis in NSCLC cells. Meanwhile, circLARP4 overexpression suppressed glycolysis in NSCLC cells, as evidenced by the reduced HK2, glucose consumption and lactate production levels. Further analyses proved a downregulation of miR-135b by circLARP4 in a ceRNA-dependent manner in NSCLC cells. CircLARP4-mediated tumor suppression on NSCLC progression was partially overturned by overexpressing miR-135b. Moreover, we confirmed that circLARP4 had antitumor effect on xenograft tumors and downregulated miR-135b. Furthermore, circLARP4 overexpression inhibited the PTEN/AKT/HIF-1α pathway in NSCLC cells and xenograft tumors by downregulating miR-135b.
Conclusion: Our findings suggested that circLARP4 suppressed NSCLC progression by sponging miR-135b through inactivation of the PTEN/AKT/HIF-1α pathway, which broadens our understanding concerning the roles of circLARP4 in NSCLC tumorigenesis.

Keywords:  HK2; circLARP4; glycolysis; miR-135b; non-small cell lung cancer; the PTEN/AKT/HIF-1α pathway

DOI:  https://doi.org/10.2147/OTT.S240399
Signal Transduct Target Ther. 2020 May 22. 5(1): 54

Hypoxia-induced GBE1 expression promotes tumor progression through metabolic reprogramming in lung adenocarcinoma.

Lifeng Li, Li Yang, Zhirui Fan, Wenhua Xue, Zhibo Shen, Yongliang Yuan, Xiangdong Sun, Dan Wang, Jingyao Lian, Liping Wang, Jie Zhao, Yi Zhang.

Hypoxia mediates a metabolic switch from oxidative phosphorylation to glycolysis and increases glycogen synthesis. We previously found that glycogen branching enzyme (GBE1) is downstream of the hypoxia-inducible factor-1 (HIF1) signaling pathway in lung adenocarcinoma (LUAD) cells; however, the molecular mechanism underlying HIF1 regulation of GBE1 expression remains unknown. Herein, the effect of GBE1 on tumor progression via changes in metabolic signaling under hypoxia in vitro and in vivo was evaluated, and GBE1-related genes from human specimens and data sets were analyzed. Hypoxia induced GBE1 upregulation in LUAD cells. GBE1-knockdown A549 cells showed impaired cell proliferation, clone formation, cell migration and invasion, angiogenesis, tumor growth, and metastasis. GBE1 mediated the metabolic reprogramming of LUAD cells. The expression of gluconeogenesis pathway molecules, especially fructose-1,6-bisphosphatase (FBP1), was markedly higher in shGBE1 A549 cells than it was in the control cells. FBP1 inhibited the tumor progression of LUAD. GBE1-mediated FBP1 suppression via promoter methylation enhanced HIF1α levels through NF-κB signaling. GBE1 may be a negative prognostic biomarker for LUAD patients. Altogether, hypoxia-induced HIF1α mediated GBE1 upregulation, suppressing FBP1 expression by promoter methylation via NF-κB signaling in LUAD cells. FBP1 blockade upregulated HIF1α, triggered the switch to anaerobic glycolysis, and enhanced glucose uptake. Therefore, targeting HIF1α/GBE1/NF-κB/FBP1 signaling may be a potential therapeutic strategy for LUAD.

DOI: https://doi.org/10.1038/s41392-020-0152-8
Cancer Lett. 2020 May 14. pii: S0304-3835(20)30227-5. [Epub ahead of print]

IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway.

Yi-Fang Yang, Yen-Yun Wang, Michael Hsiao, Steven Lo, Yu-Chan Chang, Yi-Hua Jan, Tsung-Ching Lai, Yi-Chen Lee, Ya-Ching Hsieh, Shyng-Shiou F Yuan.

  The tumor microenvironment (TME) and metabolic reprogramming have been implicated in cancer development and progression. However, the link between TME, metabolism, and cancer progression in lung cancer is unclear. In the present study, we identified IMPAD1 from the conditioned medium of highly invasive CL1-5. High expression of IMPAD1 was associated with a poorer clinical phenotype in lung cancer patients, with reduced survival and increased lymph node metastasis. Knockdown of IMPAD1 significantly inhibited migration/invasion abilities and metastasis in vitro and in vivo. Upregulation of IMPAD1 and subsequent accumulation of AMP in cells increased the pAMPK, leading to Notch1 and HEY1 upregulation. As AMP is an ADORA1 agonist, treatment with ADORA1 inhibitor reduced the expression of pAMPK and HEY1 expression in IMPAD1-overexpressing cells. IMPAD1 caused mitochondria dysfunction by inhibiting mitochondrial Complex I activity, which reduced mitochondrial ROS levels and activated the AMPK-HEY1 pathway. Collectively this study supports the multipotent role of IMPAD1 in promotion of lung cancer metastasis by simultaneously increasing AMP levels, inhibition of Complex I activity to decrease ROS levels, thereby activating AMPK-Notch1-HEY1 signaling, and providing an alternative metabolic pathway in energy stress conditions.

Keywords:  ADORA1; AMP; IMPAD1; Lung cancer; Metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2020.04.025
Biomedicines. 2020 May 14. pii: E119. [Epub ahead of print]8(5):

Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy.

Saleha Anwar, Taj Mohammad, Anas Shamsi, Aarfa Queen, Shahnaz Parveen, Suaib Luqman, Gulam Mustafa Hasan, Khalid A Alamry, Naved Azum, Abdullah M Asiri, Md Imtaiyaz Hassan.

  Design and development of potential pyruvate dehydrogenase kinase 3 (PDK3) inhibitors have gained attention because of their possible therapeutic uses in lung cancer therapy. In the present study, the binding affinity of naturally occurring alkaloids, hordenine, vincamine, tryptamine, cinchonine, and colcemid was measured with PDK3. The molecular docking and fluorescence binding studies suggested that all these compounds show a considerable binding affinity for PDK3. Among them, the affinity of hordenine to the PDK3 was excellent (K = 106 M-1) which was further complemented by isothermal titration calorimetric measurements. Hordenine binds in the active site pocket of PDK3 and forms a significant number of non-covalent interactions with functionally important residues. All-atom molecular dynamics (MD) simulation study suggested that the PDK3-hordenine complex is stabilized throughout the trajectory of 100ns and leads to fewer conformational changes. The enzyme inhibition studies showed that hordenine inhibits the activity of PDK3 with an IC50 value of 5.4 µM. Furthermore, hordenine showed a cytotoxic effect on human lung cancer cells (A549 and H1299) with an admirable IC50 value. However, it did not inhibit the growth of HEK293 cells up to 200 µM, indicating its non-toxicity to non-cancerous cell lines. In summary, our findings provide the basis for the therapeutic implication of hordenine and its derivatives in lung cancer and PDK3-related diseases after required in vivo validation.

Keywords:  drug design and discovery; hordenine; kinase inhibitors; lung cancer therapy; molecular dynamics simulation; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.3390/biomedicines8050119
Amino Acids. 2020 May 19.

Glycine metabolomic changes induced by anticancer agents in A549 cells.

Kaiqiang Guo, Yin Cao, Zan Li, Xiaoxiao Zhou, Rong Ding, Kejing Chen, Yan Liu, Yingkun Qiu, Zhen Wu, Meijuan Fang.

  Glycine plays a key role in rapidly proliferating cancer cells such as A549 cells. Targeting glycine metabolism is considered as a potential means for cancer treatment. However, the drug-induced alterations in glycine metabolism have not yet been investigated. Herein, a total of 34 glycine metabolites were examined in A549 cells with or without anticancer drug treatment. This work showed all tested anticancer agents could alter glycine metabolism in A549 cells including inhibition of pyruvate metabolism and down-regulation of betaine aldehyde and 5'-phosphoribosylglycinamide. Principal component analysis and orthogonal partial least-squares discrimination analysis exhibited the difference between control and each drug-treated group. In general, cisplatin, camptothecin, and SAHA could induce the significant down-regulation of more metabolites, compared with afatinib, gefitinib, and targretin. Both glycine, serine and threonine metabolism, and purine metabolism were significantly disturbed by the treatment with afatinib, gefitinib, and targretin. However, the treatment using cisplatin, camptothecin, and SAHA was considered to be highly responsible for the perturbation of glycine, serine and threonine metabolism, and cysteine and methionine metabolism. Finally, multivariate analysis for control and all drug-treated groups revealed 11 altered metabolites with a significant difference. It implies anti-cancer agents with different mechanisms of action might induce different comprehensive changes of glycine metabolomics. The current study provides fundamental insights into the acquisition of the role of anti-cancer agents in glycine metabolism while suppressing cancer cell proliferation, and may aid the development of cancer treatment targeting glycine metabolism.

Keywords:  A549 cell; Anti-cancer agents; Glycine; Metabolomics

DOI:  https://doi.org/10.1007/s00726-020-02853-0
ESMO Open. 2020 May;pii: e000689. [Epub ahead of print]5(3):

Evaluation of nutritional status in non-small-cell lung cancer: screening, assessment and correlation with treatment outcome.

Ilaria Trestini, Isabella Sperduti, Marco Sposito, Dzenete Kadrija, Alessandro Drudi, Alice Avancini, Daniela Tregnago, Luisa Carbognin, Chiara Bovo, Antonio Santo, Massimo Lanza, Mirko D'Onofrio, Giampaolo Tortora, Emilio Bria, Michele Milella, Sara Pilotto.

  BackgroundNutritional derangements are common hallmarks of non-small-cell lung cancer (NSCLC). Nevertheless, their early detection is overlooked in clinical routine. This study aimed to evaluate nutritional status and its correlation with outcome in NSCLC patients.MethodsData regarding NSCLC patients undergoing nutritional evaluation were prospectively collected (May 2016-October 2018). Nutritional risk was assessed by Nutritional Risk Screening 2002 (NRS-2002). Bilateral psoas major muscles were measured at L3 vertebrae level with routine staging-computed tomography and changes were evaluated using Wilcoxon signed-rank test. Clinico-pathological and nutritional data were correlated to progression-free/overall survival (PFS/OS) and response rate (ORR) using a Cox and logistic regression model. Kaplan-Meier curves were compared with log-rank test.ResultsThirty-eight patients were included. The majority (65.8%) of them were at nutritional risk (NRS-2002 ≥3). At multivariate analysis for patients with advanced disease, age (HR 2.44, p=0.05), performance status (HR 2.48, p=0.043) and NRS-2002 (HR 1.74, p=0.001) were significant independent predictors for PFS and weight loss (HR 1.07, p=0.008) for OS. Patients with baseline NRS-2002 <3 had significantly longer 1-year PFS (85.7% vs 19.4%, p=0.02) and higher ORR (66.7% vs 21.4%) than those with NRS-2002 ≥3. An explorative evaluation demonstrated that NRS-2002 score significantly decreased after nutritional intervention (p=0.001) for 3 months.ConclusionBaseline nutritional risk represents a prognostic factor in NSCLC. Nutritional counselling should be applied as a fundamental tool to improve nutritional risk in a short period, ameliorating patients' outcome.

Keywords:  muscle wasting; non-small-cell lung cancer; nutritional intervention; nutritional risk; prognosis

DOI:  https://doi.org/10.1136/esmoopen-2020-000689