bims-meluca 2020-04-05 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2020–04–05
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

KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer.
NUDT21 suppresses the growth of small cell lung cancer by modulating GLS1 splicing.
Metformin enhances cytotoxic action of dichloroacetate against Lewis lung carcinoma cells in vitro.
Transcriptome analysis reveals gender-specific differences in overall metabolic response of male and female patients in lung adenocarcinoma.
Pemetrexed sensitizes human lung cancer cells to cytotoxic immune cells.
Exercise-Mediated Lowering of Glutamine Availability Suppresses Tumor Growth and Attenuates Muscle Wasting.
Biochemical Markers of Saliva in Lung Cancer: Diagnostic and Prognostic Perspectives.
Blood Parameters Demonstrating a Significant Survival Impact in Patients With Locally Advanced NSCLC Undergoing Definitive Chemoradiotherapy.

Cancer Cell. 2020 Mar 23. pii: S1535-6108(20)30106-9. [Epub ahead of print]

KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer.

Hunain Alam, Ming Tang, Mayinuer Maitituoheti, Shilpa S Dhar, Manish Kumar, Chae Young Han, Chandrashekar R Ambati, Samir B Amin, Bingnan Gu, Tsai-Yu Chen, Yu-Hsi Lin, Jichao Chen, Florian L Muller, Nagireddy Putluri, Elsa R Flores, Francesco J DeMayo, Laura Baseler, Kunal Rai, Min Gyu Lee.

  Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicity of human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically, Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findings indicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors.

Keywords:  KMT2D; epigenetic modifier; glycolysis; histone methylation; histone methyltransferase; inhibitor; lung cancer; metabolism; super-enhancer; tumor suppressor

DOI:  https://doi.org/10.1016/j.ccell.2020.03.005
Biochem Biophys Res Commun. 2020 Mar 27. pii: S0006-291X(20)30574-X. [Epub ahead of print]

NUDT21 suppresses the growth of small cell lung cancer by modulating GLS1 splicing.

Chuan-Cheng Gao, Qin-Qin Xu, Feng-Jun Xiao, Hua Wang, Chu-Tse Wu, Li-Sheng Wang.

  The mRNA precursor 3'-end modification factor NUDT21 is a major regulator of 3'UTR shortening and an important component of pre-mRNA cleavage and polyadenylation. However, its role in pathologic progress of small cell lung cancer (SCLC) remains unclear. In this study, we observed that NUDT21 expression is downregulated in SCLC tissues. Hypoxia-induced down-regulation of NUDT21 through HIF-1α. NUDT21 shRNA transduction promotes proliferation and inhibits apoptosis of A549 cells. NUDT21 inhibition also promotes tumor growth in a mouse xenograft model. Furthermore, we clarified that HIF-1α mediated NUDT21 downregulation which altered the expression patterns of two isoforms of GLS1, GAC and KGA. These results link the hypoxic tumor environments to aberrant glutamine metabolism which is important for cellular energy in SCLC cells. Therefore, NUDT21 could be considered as a potential target for the treatment of SCLC.

Keywords:  GLS1; HIF-1α; Hypoxic; NUDT21; SCLC

DOI:  https://doi.org/10.1016/j.bbrc.2020.03.089
Exp Oncol. 2020 03;42(1): 35-39

Metformin enhances cytotoxic action of dichloroacetate against Lewis lung carcinoma cells in vitro.

D L Kolesnik, O N Pyaskovskaya, O Gorbach, G I Solyanik.

Tumor cell metabolism is considered one of the hallmarks of cancer. This concept is exploited in the development of new ways of anticancer therapy based on the use of substances capable of changing drastically bioenergetic metabolism of tumor cells. Among them, sodium dichloroace-tate (DCA), an inhibitor of pyruvate dehydrogenase kinase, and metformin (MTF), an antidiabetic hypoglycemic drug, an inhibitor of the mitochondrial respiratory chain (complex I), both have been long used in clinical non-oncological practice, and presently are considered promising candidates in oncology.
AIM: To study the capability of MTF to enhance the antitumor action of DCA against Lewis lung carcinoma cells in vitro.
MATERIALS AND METHODS: LLC/R9, a low metastatic variant of Lewis lung carcinoma cells, was used. Effects of 30 mM DCA in combination with 2 mM MTF on cell survival, cell cycle distribution, apoptosis, mitochondrial potential, intracellular ATP level, glucose consumption, and lactate production rates were determined in vitro.
RESULTS: MTF was shown to enhance the cytotoxic/cytostatic action of DCA against LLC/R9 cells in vitro. Treatment of LLC/R9 cells with 30 mM DCA in combination with 2 mM MTF resulted in a 39% decrease in the number of viable cells (p < 0.05), a 2.8-fold increase of the number of dead cells (p < 0.05), a near 2-fold decrease in the proportion of cells at the S-phase (p < 0.05), a 4-fold increase in the apoptosis (p < 0.05) and significant reduction (p < 0.05) of the mitochondrial membrane potential of tumor cells as compared to corresponding values in control. DCA alone reduced glucose consumption and lactate production rates by more than 26% (p < 0.05) and 34% (p < 0.05), respectively, whereas MTF counteracted these effects. Nevertheless, in the cells treated with both DCA and DCA in combination with MTF, the intracellular adenosine triphosphate increased by 33-35% compared with that in the control (p < 0.05).
CONCLUSION: MTF enhanced the cytotoxic/cytostatic action of DCA against LLC/R9 cells in vitro, which points on their possible synergistic antitumor action in vivo.
PLoS One. 2020 ;15(4): e0230796

Transcriptome analysis reveals gender-specific differences in overall metabolic response of male and female patients in lung adenocarcinoma.

Ya Li, Cheng-Lu He, Wen-Xing Li, Rui-Xian Zhang, Yong Duan.

BACKGROUND: Evidence from multiple studies suggests metabolic abnormalities play an important role in lung cancer. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. The present study aimed to explore differences in the global metabolic response between male and female patients in LUAD and to identify the metabolic genes associated with lung cancer susceptibility.
METHODS: Transcriptome and clinical LUAD data were acquired from The Cancer Genome Atlas (TCGA) database. Information on metabolic genes and metabolic subsystems were collected from the Recon3D human metabolic model. Two validation datasets (GSE68465 and GSE72094) were downloaded from the Gene Expression Omnibus (GEO) database. Differential expression analysis, gene set enrichment analysis and protein-protein interaction networks were used to identified key metabolic pathways and genes. Functional experiments were used to verify the effects of genes on proliferation, migration, and invasion in lung cancer cells in vitro.
RESULTS: Samples of tumors and adjacent non-tumor tissue from both male and female patients exhibited distinct global patterns of gene expression. In addition, we found large differences in methionine and cysteine metabolism, pyruvate metabolism, cholesterol metabolism, nicotinamide adenine dinucleotide (NAD) metabolism, and nuclear transport between male and female LUAD patients. We identified 34 metabolic genes associated with lung cancer susceptibility in males and 15 in females. Most of the metabolic cancer-susceptibility genes had high prediction accuracy for lung cancer (AUC > 0.9). Furthermore, both bioinformatics analysis and experimental results showed that TAOK2 was down-regulated and ASAH1 was up-regulated in male tumor tissue and female tumor tissue in LUAD. Functional experiments showed that inhibiting ASAH1 suppressed the proliferation, migration, and invasion of lung cancer cells.
CONCLUSIONS: Metabolic cancer-susceptibility genes may be used alone or in combination as diagnostic markers for LUAD. Further studies are required to elucidate the functions of these genes in LUAD.

DOI: https://doi.org/10.1371/journal.pone.0230796
Cancer Sci. 2020 Mar 31.

Pemetrexed sensitizes human lung cancer cells to cytotoxic immune cells.

Tamio Okimoto, Hitoshi Kotani, Yuichi Iida, Akira Koyanagi, Ryosuke Tanino, Yukari Tsubata, Takeshi Isobe, Mamoru Harada.

  Pemetrexed (PEM) is a useful drug that can be combined with immune checkpoint blockade therapy for treatment of patients with advanced non-small-cell lung cancer (NSCLC). However, its effects on anti-cancer immunity, especially the sensitivity of NSCLC cells to cytotoxic immune cells, have not been fully investigated. In this study, we examined the effects of PEM on the sensitivity of human NSCLC cells to two different types of cytotoxic immune cells. Pre-treatment with PEM increased the sensitivity of two NSCLC cell lines, PC9 and A549, to activated T cells and natural killer (NK) cells, and decreased the expression of anti-apoptotic proteins, including XIAP and Mcl-1. In addition, PEM treatment increased the cell surface expression of PD-L1 on PC9 cells. PEM-induced upregulation of PD-L1 on PC9 cells was at least partially ascribed to activation of ERK and the NFκB pathway. On the other hand, PEM treatment increased the expression of UL16-binding proteins (ULBPs), ligands for the NKG2D NK receptor, on PC9 and A549 cells, as well as the induction of senescence. Although the addition of anti-PD-1 antibody showed no effect on the sensitivity of PEM-treated PC9 and A549 cells to activated T cells, that of anti-NKG2D antibody decreased the enhanced sensitivity of PEM-treated A549 cells to NK cells. These results indicate that PEM can effectively sensitize human NSCLC cells toward cytotoxic immune cells with modulating the expression of immune-regulatory molecules.

Keywords:  NK cells; PD-L1; T cells; non-small-cell lung cancer; pemetrexed

DOI:  https://doi.org/10.1111/cas.14401
iScience. 2020 Mar 12. pii: S2589-0042(20)30162-0. [Epub ahead of print]23(4): 100978

Exercise-Mediated Lowering of Glutamine Availability Suppresses Tumor Growth and Attenuates Muscle Wasting.

Katrine S Pedersen, Francesco Gatto, Bo Zerahn, Jens Nielsen, Bente K Pedersen, Pernille Hojman, Julie Gehl.

  Glutamine is a central nutrient for many cancers, contributing to the generation of building blocks and energy-promoting signaling necessary for neoplastic proliferation. In this study, we hypothesized that lowering systemic glutamine levels by exercise may starve tumors, thereby contributing to the inhibitory effect of exercise on tumor growth. We demonstrate that limiting glutamine availability, either pharmacologically or physiologically by voluntary wheel running, significantly attenuated the growth of two syngeneic murine tumor models of breast cancer and lung cancer, respectively, and decreased markers of atrophic signaling in muscles from tumor-bearing mice. In continuation, wheel running completely abolished tumor-induced loss of weight and lean body mass, independently of the effect of wheel running on tumor growth. Moreover, wheel running abolished tumor-induced upregulation of muscular glutamine transporters and myostatin signaling. In conclusion, our data suggest that voluntary wheel running preserves muscle mass by counteracting muscular glutamine release and tumor-induced atrophic signaling.

Keywords:  Cancer; Physiology; Specialized Functions of Cells

DOI:  https://doi.org/10.1016/j.isci.2020.100978
Diagnostics (Basel). 2020 Mar 27. pii: E186. [Epub ahead of print]10(4):

Biochemical Markers of Saliva in Lung Cancer: Diagnostic and Prognostic Perspectives.

Lyudmila V Bel'skaya, Elena A Sarf, Victor K Kosenok, Ivan A Gundyrev.

  The aim of the work is to study the metabolic characteristics of saliva in lung cancer for use in early diagnosis and determining the prognosis of the disease. The patient group included 425 lung cancer patients, 168 patients with non-cancerous lung diseases, and 550 healthy volunteers. Saliva samples were collected from all participants in the experiment before treatment and 34 biochemical saliva parameters were determined. Participants were monitored for six years to assess survival rates. The statistical analysis was performed by means of Statistica 10.0 (StatSoft) program and R package (version 3.2.3). To construct the classifier, the Random Forest method was used; the classification quality was assessed using the cross-validation method. Prognostic factors were analyzed by multivariate analysis using Cox's proportional hazard model in a backward step-wise fashion to adjust for potential confounding factors. A complex of metabolic changes occurring in saliva in lung cancer is described. Seven biochemical parameters were identified (catalase, triene conjugates, Schiff bases, pH, sialic acids, alkaline phosphatase, chlorides), which were used to construct the classifier. The sensitivity and specificity of the method were 69.5% and 87.5%, which is practically not inferior to the diagnostic characteristics of markers routinely used in the diagnosis of lung cancer. Significant independent factors in the poor prognosis of lung cancer are imidazole compounds (ICs) above 0.478 mmol/L and salivary lactate dehydrogenase activity below 545 U/L. Saliva has been shown to have great potential for the development of diagnostic and prognostic tests for lung cancer.

Keywords:  biochemical markers; diagnostics; lung cancer; oncology; prognostic markers; saliva

DOI:  https://doi.org/10.3390/diagnostics10040186
Anticancer Res. 2020 Apr;40(4): 2319-2322

Blood Parameters Demonstrating a Significant Survival Impact in Patients With Locally Advanced NSCLC Undergoing Definitive Chemoradiotherapy.

Michael Hoffmann, Daniel Reitz, Julian Taugner, Olarn Roengvoraphoj, Lukas Käsmann, Chukwuka Eze, Monika Karin, Claus Belka, Farkhad Manapov.

   AIM: We investigated blood parameters in patients with inoperable stage III non-small cell lung cancer (NSCLC) to predict individual outcomes after definitive chemoradiotherapy (CRT).
PATIENTS AND METHODS: Blood parameters of consecutive patients undergoing definitive CRT between 2010 and 2016 for inoperable stage III NSCLC before multimodal treatment and at first follow-up were measured and analyzed.
RESULTS: Blood parameters from 99 patients were evaluated. Histologically, about 50% of patients had an adenocarcinoma. All patients received platinum-based sequential or concurrent CRT. The median total dose to the primary tumor was 60 (range=48-70) Gy. On multivariate analysis after adjustment for all co-founders, median overall survival for pre-treatment cutoffs were: lactate dehydrogenase (LDH) >250 U/l was 17 vs. 27 months [hazard ratio (HR)=2.05, 95% confidence intervaI (CI)=1.15-3.66; p=0.015], thrombocytosis >400×106/l: 11 vs. 23 months (HR=2.75, 95% CI=1.1-6.88; p=0.03), hypoalbuminemia <3.5 g/dl: 12 vs. 24 months (HR=2.42, 95% CI=1.21-4.84; p=0.013) and post-treatment neutrophilia >7×106/l: 12 vs. 27 months (HR=2.5, 95% CI=1.21-5.17; p=0.013).
CONCLUSION: Pre-treatment elevated LDH, thrombocytosis, hypoalbuminemia and post-treatment neutrophilia were associated with significantly worse overall survival in patients with inoperable stage III NSCLC treated with CRT. Patients with both pre-therapeutic elevated LDH and hypoalbuminemia demonstrated a dismal prognosis despite completion of multimodal treatment.

Keywords:  NSCLC; blood parameters; chemoradiotherapy; prognostic factor; survival

DOI:  https://doi.org/10.21873/anticanres.14198