bims-meluca 2019-02-24 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2019–02–24
six 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

Metformin promotes survivin degradation through AMPK/PKA/GSK-3β-axis in non-small cell lung cancer.
Effects of combined inhibition of STAT3 and VEGFR2 pathways on the radiosensitivity of non-small-cell lung cancer cells.
Correlation between EGFR mutation status and F18 -fluorodeoxyglucose positron emission tomography-computed tomography image features in lung adenocarcinoma.
Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non-small cell lung cancer cells.
Vascular Endothelial Growth Factor-D (VEGF-D) is Elevated in Bronchoalveolar Lavage Fluid of Patients with Lung Squamous Carcinoma.
A comprehensive analysis of WGCNA and serum metabolomics manifests the lung cancer-associated disordered glucose metabolism.

J Cell Biochem. 2019 Feb 21.

Metformin promotes survivin degradation through AMPK/PKA/GSK-3β-axis in non-small cell lung cancer.

Zhuang Luo, Wei Chen, Wenjuan Wu, Wei Luo, Tingting Zhu, Gang Guo, Liyan Zhang, Chu Wang, Min Li, Shaoqing Shi.

  Metformin, a first-line antidiabetic drug, has been reported with anticancer activities in many types of cancer. However, its molecular mechanisms remain largely unknown. As a member of inhibitor of apoptosis proteins, survivin plays an important role in the regulation of cell death. In the present study, we investigated the role of survivin in metformin-induced anticancer activity in non-small cell lung cancer in vitro. Metformin mainly induced apoptotic cell death in A549 and H460 cell lines. It remarkably suppressed the expression of survivin, decreased the stability of this protein, then promoted its proteasomal degradation. Moreover, metformin greatly suppressed protein kinase A (PKA) activity and induced its downstream glycogen synthase kinase 3β (GSK-3β) activation. PKA activators, both 8-Br-cAMP and forskolin, significantly increased the expression of survivin. Consistently both GSK-3β inhibitor LiCl and siRNA restored the expression of survivin in lung cancer cells. Furthermore, metformin induced adenosine 5'-monophosphate-activated protein kinase (AMPK) activation. Suppression of the activity of AMPK with Compound C reversed the degradation of survivin induced by metformin, and meanwhile, restored the activity of PKA and GSK-3β. These results suggest that metformin kills lung cancer cells through AMPK/PKA/GSK-3β-axis-mediated survivin degradation, providing novel insights into the anticancer effects of metformin.

Keywords:  adenosine 5′-monophosphate-activated protein kinase; glycogen synthase kinase 3β; metformin; non-small cell lung cancer; survivin

DOI:  https://doi.org/10.1002/jcb.28470
Onco Targets Ther. 2019 ;12 933-944

Effects of combined inhibition of STAT3 and VEGFR2 pathways on the radiosensitivity of non-small-cell lung cancer cells.

Chenxi Hu, Wei Zhuang, Yun Qiao, Bin Liu, Liang Liu, Kaiyuan Hui, Xiaodong Jiang.

   Purpose: The goals of this study were to determine the effects of combined inhibition of STAT3 and vascular endothelial growth factor receptor 2 (VEGFR2) pathways on the radiosensitivity of non-small-cell lung cancer (NSCLC) cells, and to assess the underlying mechanisms.
Methods: The expressions of VEGFR2, STAT3, related signaling molecules, hypoxia-inducible factor 1-alpha (HIF-1α), and cyclin D1 were determined by Western blotting. Radiosensitivity was assessed using the colony-forming assay, and cell cycle and cell death were analyzed by flow cytometry. A nude mouse xenograft tumor model of Calu-1 cells was established. The hepatorenal toxicity of the above-mentioned treatment on tumor-bearing mice was observed by H&E staining. The expression of STAT3, VEGFR2, HIF-1α, and cyclin D1 of the transplanted tumor tissues was detected by immunohistochemistry. Apoptosis of tumor tissues was evaluated by TUNEL staining.
Results: In vitro, we selected two cell lines with high expression levels of STAT3, including Calu-1 cells that exhibit high VEGFR2 expression and A549 cells that exhibit low VEGFR2 expression. When apatinib treatment was combined with S3I-201, the expression of VEGFR2, STAT3, and their downstream signaling molecules was significantly decreased (P<0.01). There was an increase in cell death and G2/M phase arrest after treatments, with the most significant changes occurring upon dual inhibition of STAT3 and VEGFR2 (P<0.01). In vivo, combined treatment of radiotherapy and dual inhibition of VEGFR2 and STAT3 was well tolerated and did not deliver additional toxicity. Compared with the control group and the radiation treatment (RT) + apatinib or RT + S3I-201 duplex group, the expression level of STAT3, p-STAT3, VEGFR2, HIF-1α, and cyclin D1 in the triple group (RT + apatinib + S3I-201) was the lowest, and the proportion of apoptotic cells was the highest (P<0.05).
Conclusion: The combined inhibition of VEGFR2 and STAT3 is effective in enhancing radiosensitizing effects in NSCLC cells.

Keywords:  STAT3; VEGFR2; non-small-cell lung cancer; radiosensitivity

DOI:  https://doi.org/10.2147/OTT.S186559
Thorac Cancer. 2019 Feb 18.

Correlation between EGFR mutation status and F18 -fluorodeoxyglucose positron emission tomography-computed tomography image features in lung adenocarcinoma.

Lei Zhu, Guotao Yin, Wei Chen, Xiaofeng Li, Xiaozhou Yu, Xiang Zhu, Wei Jiang, Chaoyang Jia, Peihe Chen, Yufan Zhang, Di Lu, Lijuan Yu, Xubin Li, Wengui Xu.

   BACKGROUND: The purpose of this study was to investigate an association between EGFR mutation status and 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (18 F-FDG PET-CT) image features in lung adenocarcinoma.
METHODS: Retrospective analysis of the data of 139 patients with lung adenocarcinoma confirmed by surgical pathology who underwent preoperative 18 F-FDG PET-CT was conducted. Correlations between EGFR mutation status, clinical characteristics, and PET-CT parameters, including the maximum standardized uptake value (SUVmax), the mean of the SUV (SUVmean), the peak of the SUV (SUVpeak) of the primary tumor, and the ratio of SUVmax between the primary tumor and the mediastinal blood pool (SUVratio), were statistically analyzed. Multivariate logistic regression analysis was performed to identify predictors of EGFR mutation. Receiver operating characteristic curves of statistical quantitative parameters were compared.
RESULTS: EGFR mutations were detected in 74 (53.2%) of the 139 lung adenocarcinomas and were more frequent in non-smoking patients. Univariate analysis showed that the SUVmax, SUVmean, SUVpeak, and SUVratio were lower in EGFR-mutated than in wild-type tumors. The receiver operating characteristic curves showed no significant differences between their diagnostic efficiencies. Multivariate logistic regression analysis showed that being a never smoker was an independent predictor of EGFR mutation.
CONCLUSION: Quantitative parameters based on 18 F-FDG PET-CT have modest power to predict the presence of EGFR mutation in lung adenocarcinoma; however, when compared to smoking history, they are not good or significant predictive factors.

Keywords:   18F-FDG; EGFR mutation; PET/CT; lung cancer

DOI:  https://doi.org/10.1111/1759-7714.12981
Mol Carcinog. 2019 Feb 20.

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non-small cell lung cancer cells.

Wenshu Chen, Kieu Chinh Do, Bryanna Saxton, Shuguang Leng, Piotr Filipczak, Mathewos Tessema, Steven A Belinsky, Yong Lin.

  Platinum anticancer agents are essential components in chemotherapeutic regimens for non-small cell lung cancer (NSCLC) patients ineligible for targeted therapy. However, platinum-based regimens have reached a plateau of therapeutic efficacy; therefore, it is critical to implement novel approaches for improvement. The hexosamine biosynthesis pathway (HBP), which produces amino-sugar N-acetyl-glucosamine (GlcNAc) for protein glycosylation, is important for protein function and cell survival. Here we show a beneficial effect by combination of cisplatin with HBP inhibition. Expression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of HBP, was increased in NSCLC cell lines and tissues. Pharmacological inhibition of GFAT activity or knockdown of GFAT impaired cell proliferation and exerted a synergistic or additive cytotoxicity to the cells treated with cisplatin. Mechanistically, GFAT positively regulated the expression of binding immunoglobulin protein (BiP; also known as glucose-regulated protein 78, GRP78), an endoplasmic reticulum chaperone involved in unfolded protein response. Suppressing GFAT activity resulted in downregulation of BiP that activated inositol-requiring enzyme 1α (IRE1α), a sensor protein of unfolded protein response, and exacerbated cisplatin-induced cell apoptosis. These data identify GFAT-mediated HBP as a target for improving platinum-based chemotherapy for NSCLC. This article is protected by copyright. All rights reserved.

Keywords:  binding immunoglobulin protein; cisplatin; glutamine:fructose-6-phosphate amidotransferase; hexosamine biosynthesis pathway; non-small cell lung cancer

DOI:  https://doi.org/10.1002/mc.22992
Clin Lab. 2019 Jan 01. 65(1):

Vascular Endothelial Growth Factor-D (VEGF-D) is Elevated in Bronchoalveolar Lavage Fluid of Patients with Lung Squamous Carcinoma.

Dan Lv, Lin Tan, Qihe Zhang, Hongying Ma, Yun Zhang, Qiaoli Zhang, Yiming Yu, Zhongbo Chen, Qunli Ding, Zaichun Deng.

BACKGROUND: Previous studies have found that vascular endothelial growth factor (VEGF) is associated with lung cancer, yet little is known about vascular endothelial growth factor-D (VEGF-D) in bronchoalveolar lavage fluid (BALF) of lung cancer patients. In this study, we aim to investigate the expression and evaluation of VEGF-D in BALF for lung cancer diagnosis.
METHODS: BALF samples were acquired from 81 patients: 40 with benign diseases and 41 with lung cancer. The expression of VEGF-D in BALF was measured using sandwich enzyme-linked immune sorbent assays (ELISA), and the evaluation of VEGF-D in BALF for lung cancer diagnosis was also investigated.
RESULTS: In the BALF samples, the levels of VEGF-D in the lung cancer group were higher than in the benign disease group; however, there was no statistical significance between the two groups (p > 0.05). In the pathological classification of lung cancer, the levels of VEGF-D in the BALF differed significantly between the lung squamous carcinoma group and the benign disease group (p < 0.05). The diagnostic accuracies of VEGF-D in BALF for discrimination between patients with squamous cell carcinoma and benign disease were reasonable based on receiver operating characteristic (ROC curve) analysis, with a corresponding sensitivity of 64.7% and specificity of 60%, respectively.
CONCLUSIONS: This study demonstrated that the detection of VEGF-D levels in BALF is a valuable diagnostic tool for lung squamous carcinoma.

DOI: https://doi.org/10.7754/Clin.Lab.2018.180712
J Cell Biochem. 2019 Feb 19.

A comprehensive analysis of WGCNA and serum metabolomics manifests the lung cancer-associated disordered glucose metabolism.

Mingchao Ding, Fang Li, Bin Wang, Guoqing Chi, Hao Liu.

  Lung cancer is a worldwide disease and highly heterogeneous at a molecular level. In this study, we both performed the pathway enrichment analysis and the transcriptome-based weighted gene coexpression network analysis (WGCNA) so as to find the critical pathways involved in lung cancer. Our analysis results indicated that genes in viability modules (0 < Z-summary < 2) selected by WGCNA were more reliable for identifying crucial pathways, while gene enrichment analysis provided a wide range of pathways with a little emphasis on target pathways for lung cancer. On the basis of genes, which were classified into various modules by WGCNA, we found a significant aberration of glucose metabolism in lung cancer cells, demonstrating that the glucose metabolism has been perturbed, especially the glycolysis pathway. Our study revealed that disordered glucose metabolism might be closely associated with the carcinogenesis of lung cancer based on the integrated analysis of WGCNA and metabolomics, which could be a potential therapeutic target for lung cancer.

Keywords:  glucose metabolism; lung cancer; metabolomics; weighted gene coexpression network analysis

DOI:  https://doi.org/10.1002/jcb.28377