bims-meluca 2019-08-25 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2019–08–25
seven 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

Targeting Metabolic Bottlenecks in Lung Cancer.
Long non-coding RNA HOTTIP promotes hypoxia-induced glycolysis through targeting miR-615-3p/HMGB3 axis in non-small cell lung cancer cells.
Predictive and Prognostic Value of 18F-fluorodeoxyglucose Uptake Combined with Thymidylate Synthase Expression in Patients with Advanced Non-Small Cell Lung Cancer.
MicroRNA-6077 enhances the sensitivity of patients-derived lung adenocarcinoma cells to anlotinib by repressing the activation of glucose transporter 1 pathway.
Galloyl esters of trans-stilbenes are inhibitors of FASN with anticancer activity on non-small cell lung cancer cells.
Hypermetabolism is an independent prognostic factor of survival in metastatic non-small cell lung cancer patients.
HSP90/AXL/eIF4E-regulated unfolded protein response as an acquired vulnerability in drug-resistant KRAS-mutant lung cancer.

Trends Cancer. 2019 Aug;pii: S2405-8033(19)30118-9. [Epub ahead of print]5(8): 457-459

Targeting Metabolic Bottlenecks in Lung Cancer.

Volkan I Sayin, Sarah E LeBoeuf, Thales Papagiannakopoulos.

  Lung cancer remains one of the most genetically complex, aggressive, and lethal solid malignancies. Understanding how distinct lung cancer mutations give rise to altered nutrient requirements and promote immune evasion in the context of a heterogeneous lung tumor microenvironment is vital for the development of novel personalized therapeutic strategies.

Keywords:  KEAP1; STK11/LKB1; immune evasion; lung cancer; metabolism; microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2019.06.001
Eur J Pharmacol. 2019 Aug 15. pii: S0014-2999(19)30567-9. [Epub ahead of print] 172615

Long non-coding RNA HOTTIP promotes hypoxia-induced glycolysis through targeting miR-615-3p/HMGB3 axis in non-small cell lung cancer cells.

Jiang Shi, Huan Wang, Wanlu Feng, Siyuan Huang, Jinlu An, Yajuan Qiu, Kai Wu.

  Increased glycolysis under hypoxic stress is a fundamentally important feature of non-small cell lung cancer (NSCLC) cells, but molecular mechanisms of hypoxia on glycolysis remain elusive. Herein, we aimed to explore whether lncRNAs and miRNAs are involved in the glycolytic reprogramming under hypoxic conditions. The levels of HOXA transcript at the distal tip (HOTTIP), miR-615-3p and high mobility group box 3 (HMGB3) mRNA were assessed by qRT-PCR. Western blot was performed to determine the protein expression of hexokinase 2 (HK-2) and HMGB3. Glucose consumption and lactate production were analyzed using a respective assay kit. The targeted correlation between miR-615-3p and HOTTIP or HMGB3 was verified using dual-luciferase reporter and RNA immunoprecipition assays. Our data revealed that HOTTIP was upregulated and miR-615-3p was downregulated in NSCLC tissues and cells. Hypoxia induced glycolysis, increased HOTTIP and HMGB3 mRNA levels and repressed miR-615-3p expression in NSCLC cells. HOTTIP deficiency or miR-615-3p expression restoration repressed hypoxia-induced glycolysis. Moreover, HOTTIP acted as a molecular sponge for miR-615-3p and HMGB3 was a direct target of miR-615-3p. The inhibitory effect of HOTTIP deficiency on glycolysis under hypoxic exposure was reversed by miR-615-3p restoration. Additionally, HOTTIP regulated HMGB3 expression by acting as a molecular sponge of miR-615-3p in NSCLC cells. In conclusion, our study suggested that HOTTIP might promote glycolysis under hypoxic conditions at least partly through regulating miR-615-3p/HMGB3 axis in NSCLC cells. Targeting HOTTIP might be a promising therapeutic strategy for NSCLC treatment.

Keywords:  Glycolysis; HMGB3; HOXA transcript at the distal tip (HOTTIP); Hypoxia; NSCLC; miR-615-3p

DOI:  https://doi.org/10.1016/j.ejphar.2019.172615
Sci Rep. 2019 Aug 21. 9(1): 12215

Predictive and Prognostic Value of 18F-fluorodeoxyglucose Uptake Combined with Thymidylate Synthase Expression in Patients with Advanced Non-Small Cell Lung Cancer.

Seung Hwan Moon, Jong-Mu Sun, Jin Seok Ahn, Keunchil Park, Byung-Tae Kim, Kyung-Han Lee, Myung-Ju Ahn, Joon Young Choi.

We investigated the relationship between tumor 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) scans and thymidylate synthase (TS) expression. In addition, we evaluated the value of FDG uptake in predicting treatment response and prognosis when combined with TS expression in patients with advanced non-small cell lung cancer (NSCLC). We measured the maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of tumor lesions on pretreatment scan in 234 patients (age: 60.1 ± 9.4 years; males: 56.4%) with stage IV non-squamous NSCLC who were enrolled in the prospective phase II clinical trial. We investigated the correlation of the parameters with TS expression and the predictive values of the parameters compared with other clinical factors. Among these parameters, TLG was the most relevant parameter that had a significant correlation with TS expression (ρ = 0.192, P = 0.008). A multivariable Cox proportional-hazards model revealed that high TLG was a significant independent predictor for treatment response (hazard ratio [HR]: 2.05; P = 0.027), progression-free survival (HR: 1.39; P = 0.043), and overall survival (HR: 1.65; P = 0.035) with other factors. In patients with advanced non-squamous NSCLC, tumor TLG on pretreatment PET/CT scan has predictive and prognostic value.

DOI: https://doi.org/10.1038/s41598-019-48674-4
Cell Signal. 2019 Aug 14. pii: S0898-6568(19)30187-1. [Epub ahead of print] 109391

MicroRNA-6077 enhances the sensitivity of patients-derived lung adenocarcinoma cells to anlotinib by repressing the activation of glucose transporter 1 pathway.

De-Bin Ma, Meng-Meng Qin, Liang Shi, Xin-Min Ding.

  Anlotinib is a novel molecular targeted agent targeting the vascular endothelial growth factor receptor, which differs from the other currently available non-small cell lung cancer (NSCLC) molecular targeted drugs targeting this receptor. Although the application of anlotinib may bring new hope for patients with advanced NSCLC, the cost of treatment is high. The results of this study showed that microRNA-6077 (miR-6077) represses the expression of GLUT1 (glucose transporter 1) and enhances the sensitivity of patient-derived lung adenocarcinoma (AC) cells to anlotinib. The miR-6077, which potentially binds to the 3'untranslated region of GLUT1, was identified and screened by miRDB, an online tool; sequences of miR-6077 were prepared as lentivirus particles. A549 cells (a lung adenocarcinoma cell line) and five patient-derived AC cell lines were infected with control miRNA or miR-6077, and subsequently treated with the indicated concentration of anlotinib. The expression of proteins, such as GLUT1, was determined by western blotting. The antitumor effect of anlotinib was identified through in-vitro (e.g., MTT) or in-vivo methods (e.g., subcutaneous tumor model). Overexpression of miR-6077 repressed the expression of GLUT1 and decreased the glucose uptake, lactate production, or ATP generation in AC cells. In addition, MiR-6077 may enhance the antitumor effect of anlotinib on A549 or patient-derived AC cell lines. Therefore, our results indicated that miR-6077 represses the expression of GLUT1 and enhances the sensitivity of patients-derived lung AC cells to anlotinib.

Keywords:  Anlotinib; GLUT1; Lung adenocarcinoma; Patient-derived cell lines; miR-6077

DOI:  https://doi.org/10.1016/j.cellsig.2019.109391
Eur J Med Chem. 2019 Aug 06. pii: S0223-5234(19)30731-7. [Epub ahead of print]182 111597

Galloyl esters of trans-stilbenes are inhibitors of FASN with anticancer activity on non-small cell lung cancer cells.

Yu-Jia Tan, Azhar Ali, Sheng-Yang Tee, Jun-Ting Teo, Yu Xi, Mei-Lin Go, Yulin Lam.

  Fatty acid synthase (FASN) is a lipogenic enzyme that is selectively upregulated in malignant cells. There is growing consensus on the oncogenicity of FASN-driven lipogenesis and the potential of FASN as a druggable target in cancer. Here, we report the synthesis and FASN inhibitory activities of two novel galloyl esters of trans-stilbene EC1 and EC5. Inhibition of FASN was accompanied by a loss in AKT activation and profound apoptosis in several non-small cell lung cancer (NSCLC) cells at the growth inhibitory concentrations of EC1 and EC5. Both FASN and phospho-AKT levels were concurrently downregulated. However, addition of a lipid concentrate to the treated cells reinstated cell viability and reversed the loss of FASN and AKT protein levels, thus recapitulating the causal relationship between FASN inhibition and the loss in cell viability.

Keywords:  Anticancer; EGCG; FASN inhibitors; Galloyl esters of trans-stilbenes; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.ejmech.2019.111597
Clin Nutr. 2019 Aug 10. pii: S0261-5614(19)30315-2. [Epub ahead of print]

Hypermetabolism is an independent prognostic factor of survival in metastatic non-small cell lung cancer patients.

Anne Jouinot, Guillaume Ulmann, Clara Vazeille, Jean-Philippe Durand, Pascaline Boudou-Rouquette, Jennifer Arrondeau, Camille Tlemsani, Ludovic Fournel, Marco Alifano, Marie Wislez, Jeanne Chapron, Camille Le Bris, Audrey Mansuet-Lupo, Diane Damotte, Nathalie Neveux, Jean-Pascal De Bandt, Jérôme Alexandre, Luc Cynober, François Goldwasser.

   BACKGROUND & AIMS: Metastatic non-small cell lung cancer (NSCLC) is the first cause of cancer death worldwide. Increased resting energy expenditure (REE) is frequent among cancer patients and may contribute to cancer cachexia. The aim of this study was to examine the prognostic value of increased REE in metastatic NSCLC patients.
METHODS: This observational study was conducted between June 2012 and November 2017 in the outpatient unit of the oncology department of Cochin hospital, Paris. Consecutive patients with newly diagnosed stage IV NSCLC underwent measurement of REE by indirect calorimetry before treatment initiation. Uni- and multivariate analysis of overall survival (OS, Cox models) included age, sex, smoking habit, histological subtype, performance status, body mass index, weight loss, albumin and CRP levels and the ratio of measured REE to the REE predicted by the Harris Benedict formula (mREE/pREE).
RESULTS: 144 patients were enrolled: mean age 64 years, 63% male, 90% non-squamous carcinoma, including 17% with ALK/EGFR alteration. In univariate analysis, tobacco consumption (p = 0.007), histo-molecular subtype (p < 10-3), performance status (p = 0.04), weight loss (p < 10-4), albumin (p < 10-4), CRP (p = 0.001) and mREE/pREE ratio (>vs ≤ 120%: HR = 2.16, p < 10-3) were significant prognostic factors of OS. Median OS were 6.1 and 17.3 months in patients with mREE/pREE ratio > and ≤120%, respectively. In multivariate analysis, histo-molecular subtype (non-squamous ALK/EGFR mutated vs squamous carcinoma: HR = 0.25, p = 0.006), weight loss (>vs ≤ 5%: HR = 1.98, p = 0.004), albumin (≥vs < 35 g/L: HR = 0.56, p = 0.02) and mREE/pREE ratio (> vs ≤120%: HR = 1.90, p = 0.004) were identified as independent prognostic factors.
CONCLUSIONS: Elevated resting energy expenditure emerges as an independent prognostic factor in metastatic NSCLC.

Keywords:  Malnutrition; Non-small cell lung cancer; Prognosis; Resting energy expenditure; Survival

DOI:  https://doi.org/10.1016/j.clnu.2019.08.003
Oncogenesis. 2019 Aug 20. 8(9): 45

HSP90/AXL/eIF4E-regulated unfolded protein response as an acquired vulnerability in drug-resistant KRAS-mutant lung cancer.

Haitang Yang, Shun-Qing Liang, Duo Xu, Zhang Yang, Thomas M Marti, Yanyun Gao, Gregor J Kocher, Heng Zhao, Ralph A Schmid, Ren-Wang Peng.

Drug resistance and tumor heterogeneity are formidable challenges in cancer medicine, which is particularly relevant for KRAS-mutant cancers, the epitome of malignant tumors recalcitrant to targeted therapy efforts and first-line chemotherapy. In this study, we delineate that KRAS-mutant lung cancer cells resistant to pemetrexed (MTA) and anti-MEK drug trametinib acquire an exquisite dependency on endoplasmic reticulum (ER) stress signaling, rendering resistant cancer cells selectively susceptible to blockage of HSP90, the receptor tyrosine kinase AXL, the eukaryotic translation initiation factor 4E (eIF4E), and the unfolded protein response (UPR). Mechanistically, acquisition of drug resistance enables KRAS-mutant lung cancer cells to bypass canonical KRAS effectors but entail hyperactive AXL/eIF4E, increased protein turnover in the ER, and adaptive activation of an ER stress-relief UPR survival pathway whose integrity is maintained by HSP90. Notably, the unique dependency and sensitivity induced by drug resistance are applicable to KRAS-mutant lung cancer cells undergoing de novo intratumor heterogeneity. In line with these findings, HSP90 inhibitors synergistically enhance antitumor effects of MTA and trametinib, validating a rational combination strategy to treat KRAS-mutant lung cancer. Collectively, these results uncover collateral vulnerabilities co-occurring with drug resistance and tumor heterogeneity, informing novel therapeutic avenues for KRAS-mutant lung cancer.

DOI: https://doi.org/10.1038/s41389-019-0158-7