bims-meluca 2020-10-11 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2020–10–11
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

Metabolic enzyme ACSL3 is a prognostic biomarker and correlates with anticancer effectiveness of statins in non-small cell lung cancer.
Altered lung tissue lipidomic profile in caspase-4 positive non-small cell lung cancer (NSCLC) patients.
A model of twenty-three metabolic-related genes predicting overall survival for lung adenocarcinoma.
High prognostic nutritional index (PNI) as a positive prognostic indicator for non-small cell lung cancer patients with bone metastasis.
FATS regulates polyamine biosynthesis by promoting ODC degradation in an ERβ-dependent manner in non-small-cell lung cancer.
Systemic Immune-inflammation Index is the Best Prognostic Factor in Patients with Advanced Stage Adenocarcinoma of the Lung Treated with Pemetrexed.

Mol Oncol. 2020 Oct 08.

Metabolic enzyme ACSL3 is a prognostic biomarker and correlates with anticancer effectiveness of statins in non-small cell lung cancer.

Lara Paula Fernández, María Merino, Gonzalo Colmenarejo, Juan Moreno-Rubio, Ruth Sánchez-Martínez, Adriana Quijada-Freire, Marta Gómez de Cedrón, Guillermo Reglero, Enrique Casado, María Sereno, Ana Ramírez de Molina.

  Lung cancer is one of the most common cancers, still characterized by high mortality rates. As lipid metabolism contributes to cancer metabolic reprogramming, several lipid metabolism genes are considered prognostic biomarkers of cancer. Statins are a class of lipid-lowering compounds used in treatment of cardiovascular disease that are currently studied for their antitumor effects. However, their exact mechanism of action and specific conditions in which they should be administered remain unclear. Here, we found that simvastatin treatment effectively promoted anti-proliferative effects and modulated lipid metabolism-related pathways in non-small cell lung cancer (NSCLC) cells, and that the anti-proliferative effects of statins were potentiated by overexpression of acyl-CoA synthetase long chain family member 3 (ACSL3). Moreover, ACSL3 overexpression was associated with worse clinical outcome in patients with high grade NSCLC. Finally, we found that patients with high expression levels of ACSL3 displayed a clinical benefit of statins treatment. Therefore, our study highlights ACSL3 as a prognostic biomarker for NSCLC, useful to select patients who would obtain a clinical benefit from statin administration.

Keywords:  Non-small cell lung cancer; cholesterol; fatty acids; lipid metabolism; statins; prognosis

DOI:  https://doi.org/10.1002/1878-0261.12816
Oncotarget. 2020 Sep 22. 11(38): 3515-3525

Altered lung tissue lipidomic profile in caspase-4 positive non-small cell lung cancer (NSCLC) patients.

Terlizzi Michela, Molino Antonio, Colarusso Chiara, Pasquale Somma, Ilaria De Rosa, Jacopo Troisi, Giovanni Scala, Rosario Salvi, Pinto Aldo, Sorrentino Rosalinda.

  Lung cancer is by far the leading cause of cancer death. Metabolomic studies have highlighted that both tumor progression and limited curative treatment options are partly due to dysregulated glucose metabolism and its associated signaling pathways. In our previous studies, we identified caspase-4 as a novel diagnostic tool for non-small cell lung cancer (NSCLC). Here, we analyzed the metabolomic profile of both plasma and tumor tissues of NSCLC patients stratified as caspase-4 positive or negative. We found that circulating caspase-4 was correlated to LDH. However, this effect was not observed in caspase-4 positive tumor tissues, where instead, fatty acid biosynthesis was favoured in that the malonic acid and the palmitic acid were higher than in non-cancerous and caspase-4 negative tissues. The glycolytic pathway in caspase-4 positive NSCLC tissues was bypassed by the malonic acid-dependent lipogenesis. On the other hand, the dysregulated glucose metabolism was regulated by a higher presence of succinate dehydrogenase (SDHA) and by the gluconeogenic valine which favoured Krebs' cycle. In conclusion, we found that the recently identified caspase-4 positive subpopulation of NSCLC patients is characterized by a lipidomic profile accompanied by alternative pathways to guarantee glucose metabolism in favour of tumor cell proliferation.

Keywords:  NSCLC; caspase-4; lipidomic; metabolomic; metabotype

DOI:  https://doi.org/10.18632/oncotarget.27724
PeerJ. 2020 ;8 e10008

A model of twenty-three metabolic-related genes predicting overall survival for lung adenocarcinoma.

Zhenyu Zhao, Boxue He, Qidong Cai, Pengfei Zhang, Xiong Peng, Yuqian Zhang, Hui Xie, Xiang Wang.

   Background: The highest rate of cancer-related deaths worldwide is from lung adenocarcinoma (LUAD) annually. Metabolism was associated with tumorigenesis and cancer development. Metabolic-related genes may be important biomarkers and metabolic therapeutic targets for LUAD.
Materials and Methods: In this study, the gleaned cohort included LUAD RNA-SEQ data from the Cancer Genome Atlas (TCGA) and corresponding clinical data (n = 445). The training cohort was utilized to model construction, and data from the Gene Expression Omnibus (GEO, GSE30219 cohort, n = 83; GEO, GSE72094, n = 393) were regarded as a testing cohort and utilized for validation. First, we used a lasso-penalized Cox regression analysis to build a new metabolic-related signature for predicting the prognosis of LUAD patients. Next, we verified the metabolic gene model by survival analysis, C-index, receiver operating characteristic (ROC) analysis. Univariate and multivariate Cox regression analyses were utilized to verify the gene signature as an independent prognostic factor. Finally, we constructed a nomogram and performed gene set enrichment analysis to facilitate subsequent clinical applications and molecular mechanism analysis.
Result: Patients with higher risk scores showed significantly associated with poorer survival. We also verified the signature can work as an independent prognostic factor for LUAD survival. The nomogram showed better clinical application performance for LUAD patient prognostic prediction. Finally, KEGG and GO pathways enrichment analyses suggested several especially enriched pathways, which may be helpful for us investigative the underlying mechanisms.

Keywords:   Dignature; Lung adenocarcinoma; Prognostic; Metabolic

DOI:  https://doi.org/10.7717/peerj.10008
Clin Respir J. 2020 Oct 09.

High prognostic nutritional index (PNI) as a positive prognostic indicator for non-small cell lung cancer patients with bone metastasis.

Shanqi Xu, Shoubo Cao, Jianxiong Geng, Chunyan Wang, Qingwei Meng, Yan Yu.

   INTRODUCTION: Increasing evidence shows the close association between prognostic nutritional index (PNI) and overall survival (OS) of solid cancers including lung cancer. However, the role of PNI in non-small cell lung cancer patients (NSCLC) with bone metastasis remains unclear.
OBJECTIVE: To explore the prognostic role of PNI in NSCLC patients with bone metastasis.
METHODS: A retrospective analysis of 259 initially diagnosed NSCLC with bone metastasis was conducted. Uni- and multivariate analysis were used to assess the potential prognostic roles of parameters.
RESULTS: The most common symptoms initially presented were cough and chest pain. Two hundred patients (77.2%) received the treatment of bisphosphonates. Patients with low PNI were found in 154 (59.5%) patients. Median survival time for all cases was 286 days. The median OS for patients with low and high PNI was 227 and 389 days, respectively. The 6-month, 1-year, and 2-year survival rates for patients with low PNI were 66.2%, 29.9% and 10.4% compared to 79.0%, 52.4% and 26.7% in patients with high PNI level. On univariate analysis, female patients, non smokers, high PNI and systematic chemotherapy (P<0.05) were shown to be closely correlated with a better prognosis of NSCLC patients with bone metastasis. Only PNI (P=0.002), systematic chemotherapy (P=0.026) and distant metastasis number (P=0.044) held statistical significance on multivariate analysis.
CONCLUSIONS: PNI represents a noninvasive, efficiency and convenient biomarker of NSCLC patients with bone metastasis. High PNI, systematic chemotherapy and distant metastasis number<2 are independent positive prognostic factors of NSCLC patients with bone metastasis.

Keywords:  NSCLC; bone metastasis; prognosis; prognostic nutritional index

DOI:  https://doi.org/10.1111/crj.13288
Cell Death Dis. 2020 Oct 09. 11(10): 839

FATS regulates polyamine biosynthesis by promoting ODC degradation in an ERβ-dependent manner in non-small-cell lung cancer.

Li Qiu, Linfei Hu, Huijuan Wang, Jinling Li, Xianhui Ruan, Bingsheng Sun, Jingtai Zhi, Xiangqian Zheng, Lin Gu, Ming Gao, Pengzhou Kong, Jun Zhang.

Polyamine biosynthesis is an essential metabolic pathway for cell growth and differentiation in non-small-cell lung cancer (NSCLC). Fragile-site associated tumour suppressor (FATS) is a novel gene involved in cancer. The results of our previous study showed that FATS-mediated polyubiquitination of p53 promotes the activation of p53 in response to DNA damage; however, little is known about the role of FATS in metabolic reprogramming in NSCLC. In the present study, FATS was observed to be significantly downregulated in NSCLC tissues compared with paired adjacent normal tissues and was associated with the survival of NSCLC patients. We further showed that the presence of the tumour suppressor FATS in NSCLC cells led to apoptosis by inducing pro-death autophagy. In addition, FATS was shown to function as a suppressor of polyamine biosynthesis by inhibiting ornithine decarboxylase (ODC) at the protein and mRNA levels, which was partially dependent on oestrogen receptor (ER). Furthermore, FATS was observed to bind to ERβ and translocate to the cytosol, leading to ODC degradation. The findings of our study demonstrate that FATS plays important roles in polyamine metabolism in NSCLC and provides a new perspective for NSCLC progression.

DOI: https://doi.org/10.1038/s41419-020-03052-1
J Coll Physicians Surg Pak. 2020 Sep;30(9): 933-939

Systemic Immune-inflammation Index is the Best Prognostic Factor in Patients with Advanced Stage Adenocarcinoma of the Lung Treated with Pemetrexed.

Irem Bilgetekin, Fatma Bugdayci Basal.

OBJECTIVE: To evaluate the prognostic role of systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in patients who received platin-pemetrexed combination therapy and/or maintenance pemetrexed therapy.
STUDY DESIGN: Observational study.
PLACE AND DURATION OF STUDY: Department of Medical Oncology, HSU Dr. Abdurrahman Yurtaslan Oncology, Training and Research Hospital, Turkey, between January 2010 and March 2020.
METHODOLOGY: Data of patients with metastatic adenocarcinoma of lung, who underwent platin-pemetrexed combination therapy and/or maintenance pemetrexed therapy retrospectively, were evaluated. Patient characteristics and disease parameters were recorded. Moreover, NLR, PLR, and SII were calculated. Survival analysis with the Kaplan-Meier and Log-rank test was performed. Cox regression analysis was used to determine independent prognostic factors of overall survivall (OS) and progression-free survival (PFS).
RESULTS: In the univariate analyses, NLR-low group and SII-low group had significantly longer PFS compared to NLR-high and SII-high groups (10 months vs. 8 months, p=0.018, and 13 months vs. 8 months, p<0.001, respectively). The significant differences were seen between SII-low and SII-high groups for OS (24 months vs. 13 months, p=0.001). In multivariate analyses, response to treatment and low-SII were independent prognostic factors for PFS (HR: 0.25, p<0.001, and HR: 0.47, p=0.002, respectively) and OS (HR: 2.09, p=0.001, and HR: 2.05, p=0.001, respectively). Conclusion: SII is the most powerful of the three studied inflammatory indices, which could independently predict overall and progression-free survival. Key Words: Systemic immune-inflammation index, Neutrophil-to-lymphocyte ratio, Platelet-to-lymphocyte ratio, Adenocarcinoma, Lung cancer, Pemetrexed.

DOI: https://doi.org/10.29271/jcpsp.2020.09.933