bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2019–09–29
eleven 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
  1. Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of non-small cell lung cancer patients.
  2. Ursolic and Oleanolic Acids Induce Mitophagy in A549 Human Lung Cancer Cells.
  3. Adaptive protein translation by the integrated stress response maintains the proliferative and migratory capacity of lung adenocarcinoma cells.
  4. KRAS-Driven Metabolic Rewiring Reveals Novel Actionable Targets in Cancer.
  5. The Pharmacogenomics "Side-Effect" of TP53/EGFR in Non-Small Cell Lung Cancer Companied with Atorvastatin Therapy: A Functional Network Analysis.
  6. Gene expression and prognosis of insulin‑like growth factor‑binding protein family members in non‑small cell lung cancer.
  7. C/EBPδ-Slug-Lox1 axis promotes metastasis of lung adenocarcinoma via oxLDL uptake.
  8. Metabolic profiles of serum samples from ground glass opacity represent potential diagnostic biomarkers for lung cancer.
  9. Fluvastatin inhibits HMG-CoA reductase and prevents non-small cell lung carcinogenesis.
  10. A combined computational pipeline to detect circular RNAs in human cancer cells under hypoxic stress.
  11. Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling.
  1. Clin Cancer Res. 2019 Sep 23. pii: clincanres.1237.2019. [Epub ahead of print]
    Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of non-small cell lung cancer patients.
    Youngtae Jeong, Jessica A Hellyer, Henning Stehr, Ngoc T Hoang, Xiaomin Niu, Millie Das, Sukhmani K Padda, Kavitha Ramchandran, Joel W Neal, Heather A Wakelee, Maximilian Diehn.
       PURPOSE: Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations which activate NFE2L2, including mutations in NFE2L2,KEAP1, or CUL3,have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored.
    EXPERIMENTAL DESIGN: We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 stage IV NSCLC patients with KEAP1, NFE2L2, or CUL3mutations and a matched cohort of 52 wildtype patients. Time to treatment failure after front line platinum doublet chemotherapy and overall survival was compared between the two groups.
    RESULTS: Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In NSCLC patients, median time to treatment failure (TTF) after first line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared to 8.3 months in the control group (p < 0.0001) Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (p = 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter time to treatment failure and overall survival after first line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of NSCLC patients are therefore needed.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-1237
  2. Molecules. 2019 Sep 23. pii: E3444. [Epub ahead of print]24(19):
    Ursolic and Oleanolic Acids Induce Mitophagy in A549 Human Lung Cancer Cells.
    Nayeli Shantal Castrejón-Jiménez, Kahiry Leyva-Paredes, Shantal Lizbeth Baltierra-Uribe, Juan Castillo-Cruz, Marcia Campillo-Navarro, Alma Delia Hernández-Pérez, Alexandra Berenice Luna-Angulo, Rommel Chacón-Salinas, Ramón Mauricio Coral-Vázquez, Iris Estrada-García, Luvia Enid Sánchez-Torres, Carlos Torres-Torres, Blanca Estela García-Pérez.
      Ursolic and oleanolic acids are natural isomeric triterpenes known for their anticancer activity. Here, we investigated the effect of triterpenes on the viability of A549 human lung cancer cells and the role of autophagy in their activity. The induction of autophagy, the mitochondrial changes and signaling pathway stimulated by triterpenes were systematically explored by confocal microscopy and western blotting. Ursolic and oleanolic acids induce autophagy in A549 cells. Ursolic acid activates AKT/mTOR pathways and oleanolic acid triggers a pathway independent on AKT. Both acids promote many mitochondrial changes, suggesting that mitochondria are targets of autophagy in a process known as mitophagy. The PINK1/Parkin axis is a pathway usually associated with mitophagy, however, the mitophagy induced by ursolic or oleanolic acid is just dependent on PINK1. Moreover, both acids induce an ROS production. The blockage of autophagy with wortmannin is responsible for a decrease of mitochondrial membrane potential (Δψ) and cell death. The wortmannin treatment causes an over-increase of p62 and Nrf2 proteins promote a detoxifying effect to rescue cells from the death conducted by ROS. In conclusion, the mitophagy and p62 protein play an important function as a survival mechanism in A549 cells and could be target to therapeutic control.
    Keywords:  A549 human lung cancer cells; PINK1/Parkin; mitophagy; oleanolic acid; reactive oxygen species; ursolic acid
    DOI:  https://doi.org/10.3390/molecules24193444
  3. Mol Cancer Res. 2019 Sep 24. pii: molcanres.0245.2019. [Epub ahead of print]
    Adaptive protein translation by the integrated stress response maintains the proliferative and migratory capacity of lung adenocarcinoma cells.
    Alexandra E Albert, Sally J Adua, Wesley L Cai, Anna Arnal-Estape, Gary W Cline, Zongzhi Liu, Minghui Zhao, Paul D Cao, Malaiyalam Mariappan, Don X Nguyen.
      The integrated stress response (ISR) is a conserved pathway which is activated by cells that are exposed to stress. In lung adenocarcinoma (LUAD), activation of the ATF4 branch of the ISR by certain oncogenic mutations has been linked to the regulation of amino acid metabolism. In the present study, we provide evidence for ATF4 activation across multiple stages and molecular subtypes of human LUAD. In response to extracellular amino acid limitation, LUAD cells with diverse genotypes commonly induce ATF4 in an eIF2α dependent manner, which can be blocked pharmacologically using the integrated stress response inhibitor (ISRIB). Although suppressing eIF2α or ATF4 can trigger different biological consequences, adaptive cell cycle progression and cell migration are particularly sensitive to inhibition of the ISR. These phenotypes require the ATF4 target gene asparagine synthetase (ASNS), which maintains protein translation independently of the mTOR/PI3K pathway. Moreover, NRF2 protein levels and oxidative stress can be modulated by the ISR downstream of ASNS. Finally, we demonstrate that ASNS controls the biosynthesis of select proteins, including the cell cycle regulator cyclin B1, which are associated with poor LUAD patient outcome. Our findings uncover new regulatory layers of the ISR pathway and its control of proteostasis in lung cancer cells. Implications: We reveal novel regulatory mechanisms by which the integrated stress response controls selective protein translation and is required for cell cycle progression and migration of lung cancer cells.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-19-0245
  4. Front Oncol. 2019 ;9 848
    KRAS-Driven Metabolic Rewiring Reveals Novel Actionable Targets in Cancer.
    Emanuela Pupo, Daniele Avanzato, Emanuele Middonti, Federico Bussolino, Letizia Lanzetti.
      Tumors driven by mutant KRAS are among the most aggressive and refractory to treatment. Unfortunately, despite the efforts, targeting alterations of this GTPase, either directly or by acting on the downstream signaling cascades, has been, so far, largely unsuccessful. However, recently, novel therapeutic opportunities are emerging based on the effect that this oncogenic lesion exerts in rewiring the cancer cell metabolism. Cancer cells that become dependent on KRAS-driven metabolic adaptations are sensitive to the inhibition of these metabolic routes, revealing novel therapeutic windows of intervention. In general, mutant KRAS fosters tumor growth by shifting cancer cell metabolism toward anabolic pathways. Depending on the tumor, KRAS-driven metabolic rewiring occurs by up-regulating rate-limiting enzymes involved in amino acid, fatty acid, or nucleotide biosynthesis, and by stimulating scavenging pathways such as macropinocytosis and autophagy, which, in turn, provide building blocks to the anabolic routes, also maintaining the energy levels and the cell redox potential (1). This review will discuss the most recent findings on mutant KRAS metabolic reliance in tumor models of pancreatic and non-small-cell lung cancer, also highlighting the role that these metabolic adaptations play in resistance to target therapy. The effects of constitutive KRAS activation in glycolysis elevation, amino acids metabolism reprogramming, fatty acid turnover, and nucleotide biosynthesis will be discussed also in the context of different genetic landscapes.
    Keywords:  KRAS; NSCLC; PDAC; gluocose metabolism in cancer; glycolysis; metabolic adaptability in cancer; metabolic rewiring
    DOI:  https://doi.org/10.3389/fonc.2019.00848
  5. Anticancer Agents Med Chem. 2019 Jul 12.
    The Pharmacogenomics "Side-Effect" of TP53/EGFR in Non-Small Cell Lung Cancer Companied with Atorvastatin Therapy: A Functional Network Analysis.
    Lei Zhang, Yifang Huang, Xuedong Gan, Siying He, Xiaohuan Cheng, Na Yang, Siwei Li, Zuhua Li, Fang Zheng.
       BACKGROUND: Atorvastatin belongs to the group of statins, which is leading drugs for hypercholesterolemia treatment. Meanwhile, its anticancer effect is emerged and highly appreciated, but the properties are still unclear. The aim of this study was to explore the underlying anticancer mechanisms induced by atorvastatin and enlarge the potential target in non-small cell lung cancer.
    METHODS: Target genes of atorvastatin were collected in the DrugBank database. Prediction of interaction between primary targets and secondary targets was performed, and protein-protein interaction network was constructed though the STRING. Then, KEGG pathway enrichment analysis was performed with WebGestalt and ClueGO, which including the pathways in non-small cell lung cancer. Furthermore, a genomic alteration analysis of the selected seed genes of atorvastatin benefit and in non-small cell lung cancer pathway was made by cBioPortal. Finally, a survival analysis with the selected seed genes in lung cancer (lung adenocarcinoma, lung squamous cell carcinoma) was conducted using Kaplan-Meier (KM) plotter.
    RESULTS: Totally, to identify seed genes, 65 potential candidate genes were screened as targets for atorvastatin using STRING with DrugBank database, while the KEGG pathway was enriched to get the overlap match of pathways in non-small cell lung cancer. Then 4 seed genes, Epidermal Growth Factor Receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (ERBB2), AKT serine/threonine kinase 1 (AKT1) and tumor protein p53 (TP53), were selected and their genomic alternation were evaluated in cBioPortal. Survival analysis found that TP53 and EGFR showed a significant correlation (log rank P = 3e-07 and 0.023) with lung adenocarcinoma and lung squamous cell carcinoma, according to KM analysis.
    CONCLUSION: Gene-phenotype connectivity for atorvastatin in non-small cell lung cancer was identified using functional/activity network analysis method, and our findings demonstrated that TP53 and EGFR could be the potential targets in cancer patients with atorvastatin therapy.
    Keywords:  AKT1 ; Atorvastatin; EGFR; TP53; functional/activity network analysis; non-small cell lung cancer
    DOI:  https://doi.org/10.2174/1871520619666190712203217
  6. Oncol Rep. 2019 Sep 16.
    Gene expression and prognosis of insulin‑like growth factor‑binding protein family members in non‑small cell lung cancer.
    Jiao Wang, Zhi-Guo Hu, Dan Li, Ji-Xion Xu, Zhen-Guo Zeng.
      Lung cancer is the leading cause of cancer mortality worldwide. Approximately 85% of all lung cancer cases are classified as non‑small cell lung cancer (NSCLC). Currently, there is no standard method to predict the survival of patients with NSCLC. Insulin‑like growth factor‑binding proteins (IGFBPs) function as modulators of IGF signaling and are attracting increasing attention for their role in NSCLC. However, the prognostic values of individual IGFBPs in NSCLC, particularly at the mRNA level, remain unknown. In the present study, the distinct expression patterns and prognostic values of IGFBP family members in patients with NSCLC through bioinformatics analysis were reported using a series of databases, including Gene Expression Profiling Interactive Analysis, Kaplan‑Meier Plotter, cBioPortal, GeneMANIA, and the Database for Annotation, Visualization and Integrated Discovery. In patients with NSCLC, IGFBP2 and IGFBP3 were significantly upregulated, while IGFBP6 was downregulated. High IGFBP1/2/4 expression was correlated with poor overall survival (OS) in all NSCLC types, especially adenocarcinoma; however, high IGFBP2/5 expression was significantly correlated with favorable OS only in patients with squamous cell carcinoma. In addition, aberrant IGFBP1/2/3/4/5 mRNA levels were associated with the prognosis of subsets of NSCLC with different clinicopathological features. These results indicated that various IGFBPs can serve as useful prognostic biomarkers and as potential targets for NSCLC therapies.
    DOI:  https://doi.org/10.3892/or.2019.7314
  7. Oncogene. 2019 Sep 27.
    C/EBPδ-Slug-Lox1 axis promotes metastasis of lung adenocarcinoma via oxLDL uptake.
    Dongmei Wang, Xinghua Cheng, Yu Li, Mingwei Guo, Wenjun Zhao, Jin Qiu, Ying Zheng, Meiyao Meng, Xiaodan Ping, Xin Chen, Shu Wang, Jian Luo, Qingquan Luo, Xinran Ma, Lingyan Xu.
      Cancer cells undergo significant lipid metabolic reprogramming to ensure sufficient energy supply for survival and progression. However, how cancer cells integrate lipid metabolic signaling with cancer progression is not well understood. In the present study, we demonstrated that C/EBPδ, a critical lipid metabolic regulator, is a TGF-β1 downstream gene and promotes lung adenocarcinoma metastasis. Importantly, C/EBPδ caused significant oscillations in both lipid metabolic and epithelial to mesenchymal transition (EMT) gene networks. Mechanistically, we demonstrated that C/EBPδ recruited oncogene NCOA3 to transcriptionally activate Slug, a canonical EMT transcription factor, which in turn induced oxLDL receptor-1 (Lox1) expression and enhanced oxLDL uptake to promote cancer metastasis, which could be blocked with LOX1 neutralizing antibody. In summary, our results unveiled a previously unappreciated interplay between lipid metabolic and metastatic program, as well as the existence of a pivotal C/EBPδ-Slug-Lox1 transcription axis to promote oxLDL levels and cancer metastasis.
    DOI:  https://doi.org/10.1038/s41388-019-1015-z
  8. Transl Lung Cancer Res. 2019 Aug;8(4): 489-499
    Metabolic profiles of serum samples from ground glass opacity represent potential diagnostic biomarkers for lung cancer.
    Jian-Zhong Li, Yuan-Yang Lai, Jian-Yong Sun, Li-Na Guan, Hong-Fei Zhang, Chen Yang, Yue-Feng Ma, Tao Liu, Wen Zhao, Xiao-Long Yan, Shao-Min Li.
       Background: Lung cancer is a leading cause of cancer deaths worldwide. Low-dose computed tomography (LDCT) screening trials indicated that LDCT is effective for the early detection of lung cancer, but the findings were accompanied by high false positive rates. Therefore, the detection of lung cancer needs complementary blood biomarker tests to reduce false positive rates.
    Methods: In order to evaluate the potential of metabolite biomarkers for diagnosing lung cancer and increasing the effectiveness of clinical interventions, serum samples from subjects participating in a low-dose CT-scan screening were analyzed by using untargeted liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). Samples were acquired from 34 lung patients with ground glass opacity diagnosed lung cancer and 39 healthy controls.
    Results: In total, we identified 9 metabolites in electron spray ionization (ESI)(+) mode and 7 metabolites in ESI(-) mode. L-(+)-gulose, phosphatidylethanolamine (PE)(22:2(13Z,16Z)/15:0), cysteinyl-glutamine, S-japonin, threoninyl-glutamine, chlorate, 3-oxoadipic acid, dukunolide A, and malonic semialdehyde levels were observed to be elevated in serum samples of lung cancer cases when compared to those of healthy controls. By contrast, 1-(2-furanylmethyl)-1H-pyrrole, 2,4-dihydroxybenzoic acid, monoethyl carbonate, guanidinosuccinic acid, pseudouridine, DIMBOA-Glc, and 4-feruloyl-1,5-quinolactone levels were lower in serum samples of lung cancer cases compared with those of healthy controls.
    Conclusions: This study demonstrates evidence of early metabolic alterations that can possibly distinguish malignant ground glass opacity from benign ground glass opacity. Further studies in larger pools of samples are warranted.
    Keywords:  L-(+)-gulose; Lung cancer; PE(22:2(13Z,16Z)/15:0); diagnostic biomarkers; ground-glass opacity; metabolites
    DOI:  https://doi.org/10.21037/tlcr.2019.07.02
  9. Cancer Prev Res (Phila). 2019 Sep 25. pii: canprevres.0211.2019. [Epub ahead of print]
    Fluvastatin inhibits HMG-CoA reductase and prevents non-small cell lung carcinogenesis.
    Tianshun Zhang, Ruihua Bai, Qiushi Wang, Keke Wang, Xiang Li, Kangdong Liu, Joohyun Ryu, Ting Wang, Xiaoyu Chang, Weiya Ma, Ann M Bode, Qingxin Xia, Yongping Song, Zigang Dong.
      Lung cancer is the leading cause of cancer death worldwide. However, promising agents for lung cancer prevention were still very limited. Identification of preventive targets and novel effective preventive agents is urgently needed for clinical applications. In the present study, we found that fluvastatin targeted 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), which a rate-limiting enzyme in the mevalonate pathway, and inhibited non-small cell lung cancer (NSCLC) tumorigenesis. Initially, we demonstrated that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo. Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft (PDX) lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-19-0211
  10. J Mol Cell Biol. 2019 Sep 27. pii: mjz094. [Epub ahead of print]
    A combined computational pipeline to detect circular RNAs in human cancer cells under hypoxic stress.
    Antonella Di Liddo, Camila de Oliveira Freitas Machado, Sandra Fischer, Stefanie Ebersberger, Andreas W Heumüller, Julia E Weigand, Michaela Müller-McNicoll, Kathi Zarnack.
      Hypoxia is associated with several diseases, including cancer. Cells that are deprived of adequate oxygen supply trigger transcriptional and posttranscriptional responses, which control cellular pathways like angiogenesis, proliferation, and metabolic adaptation. Circular RNAs (circRNAs) are a novel class of mainly non-coding RNAs that have been implicated in multiple cancers and attract increasing attention as potential biomarkers. Here, we characterize the circRNA signatures of three different cancer cell lines from cervical (HeLa), breast (MCF-7), and lung (A549) cancer under hypoxia. In order to reliably detect circRNAs, we integrate available tools with custom approaches for quantification and statistical analysis. Using this consolidated computational pipeline, we identify ~12000 circRNAs in the three cancer cell lines. Their molecular characteristics point to an involvement of complementary RNA sequences as well as trans-acting factors in circRNA biogenesis, such as the RNA-binding protein HNRNPC. Notably, we detect a number of circRNAs that are more abundant than their linear counterparts. In addition, 64 circRNAs significantly change in abundance upon hypoxia, in most cases in a cell type-specific manner. In summary, we present a comparative circRNA profiling in human cancer cell lines, which promises novel insights into the biogenesis and function of circRNAs under hypoxic stress.
    Keywords:  RNA-Seq; cancer cells; circular RNA; computational pipeline; differential expression; hypoxia
    DOI:  https://doi.org/10.1093/jmcb/mjz094
  11. Nat Commun. 2019 Sep 25. 10(1): 4363
    Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling.
    Nan Li, Yifan Wang, Shinya Neri, Yuanli Zhen, Lon Wolf R Fong, Yawei Qiao, Xu Li, Zhen Chen, Clifford Stephan, Weiye Deng, Rui Ye, Wen Jiang, Shuxing Zhang, Yonghao Yu, Mien-Chie Hung, Junjie Chen, Steven H Lin.
      The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.
    DOI:  https://doi.org/10.1038/s41467-019-12377-1
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