bims-meluca 2019-12-22 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2019–12–22
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

Does Tumor FDG-PET-Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?
TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway.
HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells.
p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis.
Alterations in plasma concentrations of energy-balance-related metabolites in patients with lung, or head & neck, cancers: Effects of radiotherapy.
Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma.
Low Expression of ASK1-Interacting Protein-1 Is Significantly Correlated with Tumor Angiogenesis and Poor Survival in Patients with Early Stage Non-Small Cell Lung Cancer.
Targeting the Mevalonate Pathway for Treating Lung Cancer.
Low pretreatment PNI correlates with worse survival in patients with stage III/IV NSCLC who received chemotherapy.
Influence of miR-199a on rats with non-small cell lung cancer via regulating the HIF-1α/VEGF signaling pathway.
NALP3 orchestrates cellular bioenergetics to facilitate non-small cell lung cancer cell growth.

Ann Thorac Surg. 2019 Dec 14. pii: S0003-4975(19)31875-2. [Epub ahead of print]

Does Tumor FDG-PET-Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?

Kemp H Kernstine, Brandon Faubert, Quyen N Do, Thomas J Rogers, Christopher T Hensley, Ling Cai, Jose Torrealba, Dwight Oliver, Jason W Waschmann, Robert E Lenkinski, Craig R Malloy, Ralph J Deberardinis.

BACKGROUND: In non-small cell lung cancer (NSCLC), fluorodeoxyglucose positron emission tomography (FDG-PET) assists in diagnosis, staging, and evaluating treatment response. One parameter of FDG-PET, the maximum standard uptake value (SUVm), is considered an objective measure of glucose uptake. However, little is known about the fate of glucose in FDG-avid lung tumors in vivo. The objective is to use stable glucose isotope tracing to determine if the SUVm predicts glycolytic metabolism, or other glucose fates in tumors.
METHODS: In this prospective IRB-approved clinical trial, 52 untreated potentially-resectable confirmed NSCLC patients underwent FDG-PET computed tomography. During surgery, the patients were infused with 13C-glucose. Blood, tumor (T) and normal lung (NL) samples were analyzed by mass spectrometry to determine 13C enrichment in glycolytic intermediates. These values were compared with clinical parameters including SUVm, maximum tumor diameter (TD), stage, grade, and MIB1/Ki67 proliferation index.
RESULTS: For each patient, 13C-enrichment in each metabolite was compared between tumor and adjacent lung. Although all tumors metabolized glucose, SUVm did not correlate with glycolytic intermediate labeling. Rather, SUVm correlated with markers indicating the use of other respiratory substrates, including lactate, and with the proliferation index.
CONCLUSIONS: SUVm does not correlate with glycolytic metabolism in human NSCLC, but does correlate with the proliferation index, suggesting that SUVm predicts glucose use by pathways other than glycolysis. These pathways may offer alternative therapeutic targets, including biosynthetic pathways required for cell proliferation. The research techniques in this study offer the opportunity to understand the relationships between SUVm, tumor metabolism, and therapeutic vulnerabilities in human NSCLCs.

DOI: https://doi.org/10.1016/j.athoracsur.2019.10.061
Cell Death Dis. 2019 Dec 20. 10(12): 959

TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway.

Su-Jin Jeon, Jun-Ho Ahn, Debasish Halder, Hyun-Soo Cho, Jung-Hwa Lim, Soo Young Jun, Jeong-Ju Lee, Ji-Yong Yoon, Min-Hyuk Choi, Cho-Rok Jung, Jin-Man Kim, Nam-Soon Kim.

Autophagy, an intracellular system of degrading damaged organelles and misfolded proteins, is essential for cancer cell survival. Despite the progress made towards understanding the mechanism, identification of novel autophagy regulators presents a major obstacle in developing anticancer therapies. Here, we examine the association between the TOR signaling pathway regulator-like (TIPRL) protein and autophagy in malignant transformation of tumors. We show that TIPRL upregulation in non-small cell lung cancer (NSCLC) potentiated autophagy activity and enabled autophagic clearance of metabolic and cellular stress, conferring a survival advantage to cancer cells. Importantly, the interaction of TIPRL with eukaryotic initiation factor 2α (eIF2α) led to eIF2α phosphorylation and activation of the eIF2α-ATF4 pathway, thereby inducing autophagy. Conversely, TIPRL depletion increased apoptosis by reducing autophagic clearance, which was markedly enhanced in TIPRL-depleted A549 xenografts treated with 2-deoxy-D-glucose. Overall, the study indicated that TIPRL is a potential regulator of autophagy and an important drug target for lung cancer therapy.

DOI: https://doi.org/10.1038/s41419-019-2190-0
J Cancer. 2019 ;10(27): 6903-6909

HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells.

Na-Jin Gu, Ming-Zhe Wu, Ling He, Xu-Bo Wang, Shiyu Wang, Xue-Shan Qiu, En-Hua Wang, Guang-Ping Wu.

  Chronic infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. In our previous studies, we found that HPV16 E6/E7 up-regulated HIF-1α at protein level and further up-regulated GLUT1 at both protein and mRNA levels in well-established lung cancer cell lines. In one of our further mechanism study, the results demonstrated that HPV16 E6/E7 up-regulated the expression of GLUT1 through HPV-LKB1-HIF-1α-GLUT1 axis. However, there are multiple pathways involved in HPV16 E6/E7 regulation of HIF-1α expression. In current study, using double directional genetic manipulation in well-established lung cancer cell lines, we showed that both E6 and E7 down-regulated the expression of RRAD at both protein and mRNA levels. Like LKB1, RRAD is one of the cancer suppressor genes. The loss of RRAD further activated NF-κB by promoted cytoplasmic p65 translocated to nucleus, and up-regulated the expression level of the p-p65 in nucleus. Furthermore, p-p65 up regulated HIF-1α and GLUT1 at both protein and mRNA levels. Thus, we proposed HPV16 E6/E7 up-regulated the expression of GLUT1 through HPV-RRAD-p65- HIF-1α- GLUT1 axis. In conclusion, we demonstrated for the first time that E6 and E7 promoted the expression of HIF-1α and GLUT1 by relieving the inhibitory effect of RRAD which resulted in the activation of NF-κB by promoting cytoplasmic p65 translocated to nucleus, and up-regulated the expression of the p-p65 in nucleus in lung cancer cells. Our findings provided new evidence to support the critical role of RRAD in the pathogenesis of HPV-related lung cancer, and suggested novel therapeutic targets.

Keywords:  Human papillomavirus (HPV); Hypoxia- inducible factor 1α (HIF-1α); NF-κB; Ras-related associated with diabetes (RRAD); glucose transporter 1 (GLUT1)

DOI:  https://doi.org/10.7150/jca.37070
Oncotarget. 2019 Dec 10. 10(65): 6997-7009

p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis.

Boxiao Ding, Alexander Haidurov, Ayesha Chawla, Anita Parmigiani, Gerarda van de Kamp, Alexandra Dalina, Fang Yuan, Jun Hee Lee, Peter M Chumakov, Steven R Grossman, Andrei V Budanov.

  SESTRINs (SESN1-3) are proteins encoded by an evolutionarily conserved gene family that plays an important role in the regulation of cell viability and metabolism in response to stress. Many of the effects of SESTRINs are mediated by negative and positive regulation of mechanistic target of rapamycin kinase complexes 1 and 2 (mTORC1 and mTORC2), respectively, that are often deregulated in human cancers where they support cell growth, proliferation, and cell viability. Besides their effects on regulation of mTORC1/2, SESTRINs also control the accumulation of reactive oxygen species, cell death, and mitophagy. SESN1 and SESN2 are transcriptional targets of tumor suppressor protein p53 and may mediate tumor suppressor activities of p53. Therefore, we conducted studies based on a mouse lung cancer model and human lung adenocarcinoma A549 cells to evaluate the potential impact of SESN1 and SESN2 on lung carcinogenesis. While we observed that expression of SESN1 and SESN2 is often decreased in human tumors, inactivation of Sesn2 in mice positively regulates tumor growth through a mechanism associated with activation of AKT, while knockout of Sesn1 has no additional impact on carcinogenesis in Sesn2-deficient mice. However, inactivation of SESN1 and/or SESN2 in A549 cells accelerates cell proliferation and imparts resistance to cell death in response to glucose starvation. We propose that despite their contribution to early tumor growth, SESTRINs might suppress late stages of carcinogenesis through inhibition of cell proliferation or activation of cell death in conditions of nutrient deficiency.

Keywords:  SESTRINs; lung cancer; mTORC1/2; mouse model; tumor suppression

DOI:  https://doi.org/10.18632/oncotarget.27367
J Proteomics. 2019 Dec 11. pii: S1874-3919(19)30377-X. [Epub ahead of print]213 103605

Alterations in plasma concentrations of energy-balance-related metabolites in patients with lung, or head & neck, cancers: Effects of radiotherapy.

Elisabet Rodríguez-Tomàs, Mònica Arguís, Meritxell Arenas, Salvador Fernández-Arroyo, Mauricio Murcia, Sebastià Sabater, Laura Torres, Gerard Baiges-Gayà, Anna Hernández-Aguilera, Jordi Camps, Jorge Joven.

  We investigated the alterations in the plasma concentrations of energy-balance-related metabolites in patients with lung (LC) or head & neck (HNC) cancer and the changes on these parameters induced by radiotherapy. The study was conducted in 33 patients with non-small cell LC and 28 patients with HNC. We analyzed the concentrations of 17 metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted gas chromatography coupled to quadrupole time-of-flight mass spectrometry. For comparison, a control group of 50 healthy individuals was included in the present study. Patients with LC or HNC had significant alterations in the plasma levels of several energy-balance-related metabolites. Radiotherapy partially normalized these alterations in patients with LC, but not in those with HNC. The measurement of plasma glutamate concentration was an excellent predictor of the presence of LC or HNC, with sensitivity >90% and specificity >80%. Also, associations with disease prognosis were observed with plasma glutamate, amino acids and β-hydroxybutyrate concentrations. SIGNIFICANCE: This study analyzed the changes produced in the plasma concentrations of energy-balance-related metabolites in patients with lung cancer or head and neck cancer. The results obtained identified glutamate as the parameter with the highest discrimination capacity between patients and the control group. The relationships between various metabolites and clinical outcomes were also analyzed. These results extend the knowledge of metabolic alterations in cancer, thus facilitating the search for biomarkers and therapeutic targets.

Keywords:  Cancer metabolism; Glutamate; Metabolomics; Radiotherapy; β-Hydroxybutyrate

DOI:  https://doi.org/10.1016/j.jprot.2019.103605
J Transl Med. 2019 Dec 17. 17(1): 423

Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma.

Lei Zhang, Zhe Zhang, Zhenglun Yu.

   BACKGROUND: Lung cancer (LC) is one of the most lethal and most prevalent malignant tumors, and its incidence and mortality are increasing annually. Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Several biomarkers have been confirmed by data excavation to be related to metastasis, prognosis and survival. However, the moderate predictive effect of a single gene biomarker is not sufficient. Thus, we aimed to identify new gene signatures to better predict the possibility of LUAD.
METHODS: Using an mRNA-mining approach, we performed mRNA expression profiling in large LUAD cohorts (n = 522) from The Cancer Genome Atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed, and connections between genes and glycolysis were found in the Cox proportional regression model.
RESULTS: We confirmed a set of nine genes (HMMR, B4GALT1, SLC16A3, ANGPTL4, EXT1, GPC1, RBCK1, SOD1, and AGRN) that were significantly associated with metastasis and overall survival (OS) in the test series. Based on this nine-gene signature, the patients in the test series could be divided into high-risk and low-risk groups. Additionally, multivariate Cox regression analysis revealed that the prognostic power of the nine-gene signature is independent of clinical factors.
CONCLUSION: Our study reveals a connection between the nine-gene signature and glycolysis. This research also provides novel insights into the mechanisms underlying glycolysis and offers a novel biomarker of a poor prognosis and metastasis for LUAD patients.

Keywords:  Glycolysis; Lung adenocarcinoma; Meta-analysis survival; Metastasis; Prognostic; mRNAs

DOI:  https://doi.org/10.1186/s12967-019-02173-2
Onco Targets Ther. 2019 ;12 10739-10747

Low Expression of ASK1-Interacting Protein-1 Is Significantly Correlated with Tumor Angiogenesis and Poor Survival in Patients with Early Stage Non-Small Cell Lung Cancer.

Chengyu Chen, Qun Geng, Dongfeng Sun, Wensi Hu, Chenxi Zhong, Limin Fan, Xiaoming Song.

   Objective: To investigate the expression of tumor suppressor protein ASK1-interacting protein-1 (AIP1) in cancer tissues of patients with early-stage non-small cell lung cancer (NSCLC) and its correlation with tumor progression, tumor angiogenesis and prognosis.
Methods: A total of 136 patients with stage I NSCLC who underwent radical resection of lung cancer in Qianfoshan Hospital of Shandong Province from January 2011 to December 2011 were enrolled. Immunohistochemistry was used to detect AIP1 protein in tumor tissues. Vascular endothelial CD34 immunohistochemical staining was used to count intratumoral microvessel density (MVD). SPSS 19.0 software was used to analyze the relationship between AIP1 protein expression and clinicopathological features, tumor angiogenesis and prognosis.
Results: Low expression of AIP1 was more common in tumor tissues with high MVD, and patients with low expression of AIP1 were more likely to have tumor recurrence. Multivariate analysis showed that low expression of AIP1 had predictive value for overall survival, disease-free survival, and disease-specific survival.
Conclusion: Downregulation of AIP1 protein expression is associated with lung cancer progression, tumor angiogenesis and poor prognosis. Consequently, AIP1 may prove to be an important predictor of recovery from lung cancer and could become a new therapeutic target for lung cancer treatment.

Keywords:  ASK1-interacting protein-1; NSCLC; angiogenesis; prognosis

DOI:  https://doi.org/10.2147/OTT.S222332
Am J Clin Oncol. 2020 Jan;43(1): 69-70

Targeting the Mevalonate Pathway for Treating Lung Cancer.

Ali Fatehi Hassanabad, Fady Mina.

The mevalonate (MVA) pathway is a key metabolic pathway involved in various important cellular functions. Its downstream products are critical for cell-signaling, cell membrane integrity, protein synthesis, and cellular respiration. The rate-limiting enzyme of this pathway is targeted by statins, a class of medications best known for their lipid-lowering effects. Many studies have shown that a variety of cancerous cells have a dysregulated MVA pathway. Lung cancer is responsible for a third of all cancer-related deaths worldwide. As our understanding of the molecular mechanisms driving the pathogenesis of lung cancer improves, newer therapeutics have been proposed. However, these medications have not had the expected benefits for all subtypes of lung cancer. Therefore, there exists a significant role in identifying medications with safe profiles, which can potentially be used in managing various types of lung cancer. Herein, we review whether there is a role in utilizing statins to target the MVA pathway in treating lung cancer.

DOI: https://doi.org/10.1097/COC.0000000000000630
Neoplasma. 2019 Dec 17. pii: 190401N284. [Epub ahead of print]

Low pretreatment PNI correlates with worse survival in patients with stage III/IV NSCLC who received chemotherapy.

Y Shen, H Li, Z Q Yuan, M Y Ren, S L Yu, Y D Liao, J J Cai, C Liu, B C Chen, A H Wu, G F Li, L Xie.

The aim of this study was to investigate the prognostic value of the prognostic nutritional index (PNI) on the long-term survival of non-small cell lung cancer (NSCLC) patients who received platinum-based chemotherapy. Data on nutritional parameters and clinicopathological characteristics [e.g., albumin, total protein, body mass index (BMI), eastern cooperative oncology group (ECOG) performance status, stage, pathology, treatment strategy] were analyzed and retrospectively correlated with overall survival (OS). The PNI was calculated based on the concentration of albumin and lymphocyte count [10 × albumin, (g/dl) + 0.005 × lymphocyte (count/mm3)]. A receiver operating characteristic curve (ROC) analysis was used to find the optimal cut-off value of PNI. Univariate and multivariate analyses were used to evaluate the prognostic value of PNI. A total of 186 patients met the inclusion criteria. The optimal cut-off value for PNI was 50.45. Compared with the parameters of the low PNI group (n = 76), high PNI was significantly associated with adenocarcinoma type, stage III, better ECOG and comprehensive treatment modality. The univariate analysis demonstrated that OS was superior when PNI ≥ 50.45, albumin ≥ 35 g/l, platelet-lymphocyte ratio (PLR) ≥ 163, and ECOG < 2 and when the patient received a comprehensive treatment modality. In the multivariate analysis, PNI, TNM stage and treatment strategy were identified as independent predictors of survival in this study. This retrospective study demonstrated that a low PNI was related to worse overall survival in patients with stage III/IV NSCLC who received platinum-based chemotherapy. These data provided a conceptual basis for further research on the clinical application of the PNI index for patients receiving chemotherapy for intermediate- and advanced-stage NSCLC.

DOI: https://doi.org/10.4149/neo_2019_190401N284
Eur Rev Med Pharmacol Sci. 2019 Dec;pii: 19675. [Epub ahead of print]23(23): 10363-10369

Influence of miR-199a on rats with non-small cell lung cancer via regulating the HIF-1α/VEGF signaling pathway.

L-M Wang, L-L Zhang, L-W Wang, L Zhu, X-X Ma.

OBJECTIVE: Micro-ribonucleic acids (miRNAs) are involved in the occurrence of various cancers, and the hypoxia-inducible factor 1-α (HIF-1α) is the main regulator of cell proliferation induced by hypoxia. The relationships of miR-199a and HIF-1α expressions with non-small cell lung cancer (NSCLC) remain unclear, so they were explored in this work.
MATERIALS AND METHODS: On the basis of establishing the rat model of NSCLC, the messenger RNA (mRNA) expressions of miR-199a, HIF-1α and the vascular endothelial growth factor (VEGF) were analyzed in NSCLC rats, and the correlations of miR-199a with the mRNAs of HIF-1α and VEGF and cancer staging were investigated. To further study the role of miR-199a in NSCLC cell proliferation via the HIF-1α/VEGF signaling pathway, NSCLC cells were treated with the signaling pathway inhibitor and transfected with miR-199a mimics, respectively. Also, the roles of the inhibitor PX-478 and miR-199a mimics in the expressions of miR-199a, HIF-1α, and VEGF proteins, as well as their influences on cell proliferation ability were detected.
RESULTS: In NSCLC rats, the expression of miR-199a was substantially decreased (p<0.01), but the expressions of HIF-1α and VEGF were notably raised (p<0.01). MiR-199a was negatively correlated with the expression of VEGF. As cancer developed, the expression of miR-199a was gradually lowered, but the expressions of HIF-1α and VEGF were gradually increased. Both HIF-1α/VEGF signaling pathway inhibitor PX-478 and miR-199a mimics significantly reduced the expressions of HIF-1α and VEGF proteins (p<0.01) and suppressed the cell proliferation activity.
CONCLUSIONS: MiR-199a prevents the proliferation of NSCLC cells via the targeted down-regulation of the HIF-1α/VEGF signaling pathway.

DOI: https://doi.org/10.26355/eurrev_201912_19675
Life Sci. 2019 Dec 12. pii: S0024-3205(19)31093-8. [Epub ahead of print] 117165

NALP3 orchestrates cellular bioenergetics to facilitate non-small cell lung cancer cell growth.

Zhi-Feng He, Xu-Ru Jin, Jing-Jing Lin, Xiang Zhang, Yu Liu, Hong-Lei Xu, De-Yao Xie.

   AIMS: Previous work has reported the closely correlation between inflammation and carcinogenesis, while the role of NALP3, the key component of inflammasome activation in NSCLC remains elusive. This study was to unravel the mechanism of NALP3 on modulating NSCLC cancer cell growth.
METHODS: IHC and immuno-blot were performed to analyze expression of NALP3 and indicated molecules. CCK-8 and xenograft nude mice assay were used to evaluate cell growth in vitro and in vivo. Bioenergetics assay was performed to measure OXPHOS and aerobic glycolysis. siRNA and shRNA were constructed to knockdown endogenous NALP3 and DNMT1. Co-immunoprecipitation was applied to confirm the interaction between NALP3 and DMAP1. BioProfile FLEX analyzer and Lactate Reagent Kit were used to measure relative level glucose uptake and lactate production.
KEY FINDINGS: We reported NALP3 were up-regulated in NSCLC tumor tissues. NALP3 depletion suppressed cancer cell growth in vitro and in vivo. Moreover, data showed depletion of NALP3 promoted cell bioenergetics switch from aerobic glycolysis to OXPHOS. Additionally, we found NALP3 interacted with DMAP1 and alteration of NALP3 increased DNMT1 level. Subsequently, we clarified depletion of DNMT1 significantly suppressed NSCLC cell growth and orchestrated cellular metabolism which was similar to the effects of NALP3 knockdown. Finally, our data showed high NALP3 was associated with poor outcomes, and correlated with TNM stage and differentiation.
SIGNIFICANCE: Current study elucidated NALP3 could promote metabolic reprogramming to regulate NSCLC cell growth and suggested that NALP3 may be considered as a novel biomarker and therapeutic target for NSCLC patients.

Keywords:  Cellular bioenergetics; DNMT1; Metabolic reprogramming; NALP3; Warburg effect

DOI:  https://doi.org/10.1016/j.lfs.2019.117165