bims-meluca 2019-12-08 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2019–12–08
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

Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer.
Cisplatin-resistant A549 non-small cell lung cancer cells can be identified by increased mitochondrial mass and are sensitive to pemetrexed treatment.
The Metabolic Landscape of Lung Cancer: New Insights in a Disturbed Glucose Metabolism.
Metformin mediated microRNA-7 upregulation inhibits growth, migration, and invasion of non-small cell lung cancer A549 cells.
Knock-down of PSAT1 Enhances Sensitivity of NSCLC Cells to Glutamine-limiting Conditions.
Metabolic Remodelling: An Accomplice for New Therapeutic Strategies to Fight Lung Cancer.
CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation.
Differences in the early stage gene expression profiles of lung adenocarcinoma and lung squamous cell carcinoma.

Nat Commun. 2019 Dec 06. 10(1): 5604

Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer.

Alba Luengo, Keene L Abbott, Shawn M Davidson, Aaron M Hosios, Brandon Faubert, Sze Ham Chan, Elizaveta Freinkman, Lauren G Zacharias, Thomas P Mathews, Clary B Clish, Ralph J DeBerardinis, Caroline A Lewis, Matthew G Vander Heiden.

Increased glucose uptake and metabolism is a prominent phenotype of most cancers, but efforts to clinically target this metabolic alteration have been challenging. Here, we present evidence that lactoylglutathione (LGSH), a byproduct of methylglyoxal detoxification, is elevated in both human and murine non-small cell lung cancers (NSCLC). Methylglyoxal is a reactive metabolite byproduct of glycolysis that reacts non-enzymatically with nucleophiles in cells, including basic amino acids, and reduces cellular fitness. Detoxification of methylglyoxal requires reduced glutathione (GSH), which accumulates to high levels in NSCLC relative to normal lung. Ablation of the methylglyoxal detoxification enzyme glyoxalase I (Glo1) potentiates methylglyoxal sensitivity and reduces tumor growth in mice, arguing that targeting pathways involved in detoxification of reactive metabolites is an approach to exploit the consequences of increased glucose metabolism in cancer.

DOI: https://doi.org/10.1038/s41467-019-13419-4
Cancer Cell Int. 2019 ;19 317

Cisplatin-resistant A549 non-small cell lung cancer cells can be identified by increased mitochondrial mass and are sensitive to pemetrexed treatment.

Yanyun Gao, Patrick Dorn, Shengchen Liu, Haibin Deng, Sean R R Hall, Ren-Wang Peng, Ralph A Schmid, Thomas M Marti.

   Background: Cisplatin plus pemetrexed combination therapy is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer (NSCLC). However, advanced NSCLC has a 5-year survival rate of below 10%, which is mainly due to therapy resistance. We previously showed that the NSCLC cell line A549 harbors different subpopulations including a mesenchymal-like subpopulation characterized by increased chemo- and radiotherapy resistance. Recently, therapy resistance in hematological and solid tumors has been associated with increased mitochondrial activity. Thus, the aim of this study was to investigate the role of the mitochondrial activity in NSCLC chemotherapy resistance.
Methods: Based on MitoTracker staining, subpopulations characterized by the highest 10% (Mito-High) or lowest 10% (Mito-Low) mitochondrial mass content were sorted by FACS (Fluorescence-Activated Cell Sorting) from paraclonal cultures of the NSCLC A549 cell line . Mitochondrial DNA copy numbers were quantified by real-time PCR whereas basal cellular respiration was measured by high-resolution respirometry. Cisplatin and pemetrexed response were quantified by proliferation and colony formation assay.
Results: Pemetrexed treatment of parental A549 cells increased mitochondrial mass over time. FACS-sorted paraclonal Mito-High cells featured increased mitochondrial mass and mitochondrial DNA copy number compared to the Mito-Low cells. Paraclonal Mito-High cells featured an increased proliferation rate and were significantly more resistant to cisplatin treatment than Mito-Low cells. Interestingly, cisplatin-resistant, paraclonal Mito-High cells were significantly more sensitive to pemetrexed treatment than Mito-Low cells. We provide a working model explaining the molecular mechanism underlying the increased cisplatin- and decreased pemetrexed resistance of a distinct subpopulation characterized by high mitochondrial mass.
Conclusions: This study revealed that cisplatin resistant A549 lung cancer cells can be identified by their increased levels of mitochondrial mass. However, Mito-High cells feature an increased sensitivity to pemetrexed treatment. Thus, pemetrexed and cisplatin target reciprocal lung cancer subpopulations, which could explain the increased efficacy of the combination therapy in the clinical setting.

Keywords:  Chemotherapy; Cisplatin; Lung cancer; Mitochondrial activity; Mitochondrial mass; NSCLC; Pemetrexed; Resistance

DOI:  https://doi.org/10.1186/s12935-019-1037-1
Front Oncol. 2019 ;9 1215

The Metabolic Landscape of Lung Cancer: New Insights in a Disturbed Glucose Metabolism.

Karolien Vanhove, Geert-Jan Graulus, Liesbet Mesotten, Michiel Thomeer, Elien Derveaux, Jean-Paul Noben, Wanda Guedens, Peter Adriaensens.

  Metabolism encompasses the biochemical processes that allow healthy cells to keep energy, redox balance and building blocks required for cell development, survival, and proliferation steady. Malignant cells are well-documented to reprogram their metabolism and energy production networks to support rapid proliferation and survival in harsh conditions via mutations in oncogenes and inactivation of tumor suppressor genes. Despite the histologic and genetic heterogeneity of tumors, a common set of metabolic pathways sustain the high proliferation rates observed in cancer cells. This review with a focus on lung cancer covers several fundamental principles of the disturbed glucose metabolism, such as the "Warburg" effect, the importance of the glycolysis and its branching pathways, the unanticipated gluconeogenesis and mitochondrial metabolism. Furthermore, we highlight our current understanding of the disturbed glucose metabolism and how this might result in the development of new treatments.

Keywords:  genetic alterations; glucose; lung cancer; metabolism; targeting metabolism

DOI:  https://doi.org/10.3389/fonc.2019.01215
Anticancer Drugs. 2019 Nov 25.

Metformin mediated microRNA-7 upregulation inhibits growth, migration, and invasion of non-small cell lung cancer A549 cells.

Jingying Dong, Heng Peng, Xiaolong Yang, Wenbing Wu, Yanan Zhao, Dan Chen, Lihong Chen, Ji Liu.

Metformin, a medication widely used in the treatment of type 2 diabetes mellitus, has a possible antitumor effect in type 2 diabetes mellitus patients. MicroRNA-7 is a significant microRNA in non-small cell lung cancer. Metformin has an inhibitory effect on lung cancer and regulates the expression of certain microRNAs, but there is no report connecting metformin with microRNA-7 in lung cancer. Thus, we used qPCR to measure microRNA-7 expression in A549 non-small cell lung cancer cells treated with metformin. We used CCK8, cell scratch, and Transwell assays to test the growth, migration, and invasion of A549 cells. Western blotting was used to measure the expression level of relevant proteins in A549 cells. We found that microRNA-7 was dramatically upregulated by metformin via AMPK in a dose- and time-dependent manner. Both metformin and microRNA-7 mimic reduced A549 cell growth, migration, and invasion. Metformin downregulated the levels of p-NF-κB p65, p-Erk1/2, p-AKT, and p-mTOR proteins. And the treatment with the microRNA-7 mimic had the same result. The decrease of these proteins caused the inhibition of A549 cell growth, migration, and invasion. Our discovery revealed that metformin, via increasing the expression of microRNA-7 mediated by AMPK, regulates the AKT/mTOR, MAPK/Erk, and NF-κB signaling pathways, thereby suppressing A549 cell growth, migration, and invasion.

DOI: https://doi.org/10.1097/CAD.0000000000000875
Anticancer Res. 2019 Dec;39(12): 6723-6730

Knock-down of PSAT1 Enhances Sensitivity of NSCLC Cells to Glutamine-limiting Conditions.

Hyeon-Ok Jin, Sung-Eun Hong, Ji-Young Kim, Se-Kyeong Jang, Young-Sun Kim, Ju-Hee Sim, Ac-Chin Oh, Heyjin Kim, Young Jun Hong, Jin-Kyung Lee, In-Chul Park.

   BACKGROUND/AIM: Phosphoserine aminotransferase 1 (PSAT1) is an enzyme implicated in serine biosynthesis, and its overexpression has been linked to cancer cell proliferation. Therefore, targeting PSAT1 is considered to be an anticancer strategy.
MATERIALS AND METHODS: The viability of non-small cell lung cancer (NSCLC) cells was measured by MTT assay. Protein and mRNA expression were determined by western blot and reverse transcription polymerase chain reaction, respectively.
RESULTS: Glutamine-limiting conditions were generated through glutamine deprivation or CB-839 treatment, which induced PSAT1 expression in NSCLC cells. PSAT1 expression induced by glutamine-limiting conditions was regulated by activating transcription factor 4. Knock-down of PSAT1 enhanced the sensitivity of NSCLC cells to glutamine-limiting conditions. Interestingly, ionizing radiation induced PSAT1 expression, and knocking down PSAT1 increased cell sensitivity to ionizing radiation.
CONCLUSION: Inhibiting PSAT1 might aid in the treatment of lung cancer, and PSAT1 may be a therapeutic target for lung cancer.

Keywords:  Activating transcription factor 4; glutamine; ionizing radiation; non-small cell lung cancer; phosphoserine aminotransferase 1

DOI:  https://doi.org/10.21873/anticanres.13887
Antioxidants (Basel). 2019 Nov 29. pii: E603. [Epub ahead of print]8(12):

Metabolic Remodelling: An Accomplice for New Therapeutic Strategies to Fight Lung Cancer.

Cindy Mendes, Jacinta Serpa.

  Metabolic remodelling is a hallmark of cancer, however little has been unravelled in its role in chemoresistance, which is a major hurdle to cancer control. Lung cancer is a leading cause of death by cancer, mainly due to the diagnosis at an advanced stage and to the development of resistance to therapy. Targeted therapeutic agents combined with comprehensive drugs are commonly used to treat lung cancer. However, resistance mechanisms are difficult to avoid. In this review, we will address some of those therapeutic regimens, resistance mechanisms that are eventually developed by lung cancer cells, metabolic alterations that have already been described in lung cancer and putative new therapeutic strategies, and the integration of conventional drugs and genetic and metabolic-targeted therapies. The oxidative stress is pivotal in this whole network. A better understanding of cancer cell metabolism and molecular adaptations underlying resistance mechanisms will provide clues to design new therapeutic strategies, including the combination of chemotherapeutic and targeted agents, considering metabolic intervenients. As cancer cells undergo a constant metabolic adaptive drift, therapeutic regimens must constantly adapt.

Keywords:  cancer metabolism; lung cancer; new therapeutic strategies; reactive oxygen species (ROS); therapy resistance

DOI:  https://doi.org/10.3390/antiox8120603
Life Sci Alliance. 2019 Dec;pii: e201900460. [Epub ahead of print]2(6):

CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation.

Evangelia Chavdoula, David M Habiel, Eugenia Roupakia, Georgios S Markopoulos, Eleni Vasilaki, Antonis Kokkalis, Alexander P Polyzos, Haralabia Boleti, Dimitris Thanos, Apostolos Klinakis, Evangelos Kolettas, Kenneth B Marcu.

Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non-small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-α acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKα ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKKα loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-β instead acts as a tumor promoter in this same context. IKKα knockdown in three independent human NSCLC lines (independent of K-Ras or p53 status) enhances their growth as tumor xenografts in immune-compromised mice. Bioinformatics analysis of whole transcriptome profiling followed by quantitative protein and targeted gene expression validation experiments reveals that IKKα loss can result in the up-regulation of activated HIF-1-α protein to enhance NSCLC tumor growth under hypoxic conditions in vivo.

DOI: https://doi.org/10.26508/lsa.201900460
Oncol Lett. 2019 Dec;18(6): 6572-6582

Differences in the early stage gene expression profiles of lung adenocarcinoma and lung squamous cell carcinoma.

Nitin Venugopal, Justin Yeh, Sai Karthik Kodeboyina, Tae Jin Lee, Shruti Sharma, Nikhil Patel, Ashok Sharma.

  The discovery of lung carcinoma subtype-specific gene expression changes has the potential to elucidate the molecular differences and provide personalized therapeutic targets for these pathologies. The aim of the present study was to characterize the genetic profiles of the early stages (IA/IB) of two non-small cell lung cancer subtypes, adenocarcinoma (AD) and squamous cell carcinoma (SC). RNA-Seq gene expression data from The Cancer Genome Atlas was analyzed to compare the gene expression differences between AD and SC. The gene sets specific to each subtype were further analyzed to identify the enriched Gene Ontology terms, Kyoto Encyclopedia of Genes and Genomes pathways and biological functions. The results demonstrated that a unique set of genes (145 upregulated and 27 downregulated) was altered in AD, but not in SC; another set of genes (146 upregulated and 103 downregulated) was significantly altered in SC, but not in AD. Genes highly upregulated specifically in AD included albumin (1,732-fold), protein lin-28 homolog A, which is a positive regulator of cyclin-dependent kinase 2 (150-fold) and gastric lipase (81-fold). Genes highly upregulated specifically in SC included amelotin (618-fold), alcohol dehydrogenase 7 (57-fold), aclerosteosis (55-fold) and claudin-22 (54-fold). Several cancer/testis antigen family genes were notably upregulated in SC, but not in AD, whereas mucins were upregulated only in AD. Functional pathway analysis demonstrated that the dysregulation of genes associated with retinoid X receptors was common in AD and SC, genes associated with 'lipid metabolism' and 'drug metabolism' were dysregulated only in SC, whereas genes associated with 'molecular transport' and 'cellular growth and proliferation' were significantly enriched in AD specifically. These results reveal fundamental differences in the gene expression profiles of early-stage AD and SC. In addition, the present study identified molecular pathways that are uniquely associated with the pathogenesis of these subtypes.

Keywords:  The Cancer Genome Atlas; lung adenocarcinoma; lung squamous cell carcinoma; non-small cell lung cancer

DOI:  https://doi.org/10.3892/ol.2019.11013