bims-meluca 2021-08-08 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–08–08
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

Prognosis of Non-small-cell Lung Cancer Patients With Lipid Metabolism Pathway Alternations to Immunotherapy.
LncRNA XIST Contributes to Cisplatin Resistance of Lung Cancer Cells by Promoting Cellular Glycolysis through Sponging miR-101-3p.
Preliminary evaluation of anticancer efficacy of pioglitazone combined with celecoxib for the treatment of non-small cell lung cancer.
High-Throughput Salivary Metabolite Profiling on an Ultralow Noise Tip-Enhanced Laser Desorption Ionization Mass Spectrometry Platform for Noninvasive Diagnosis of Early Lung Cancer.
Screening and identification of potential novel lipid biomarkers for non-small cell lung cancer using UPLC-MS / MS.
The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer.
Angiogenic activities are increased via upregulation of HIF-1α expression in gefitinib-resistant non-small cell lung carcinoma cells.

Front Genet. 2021 ;12 646362

Prognosis of Non-small-cell Lung Cancer Patients With Lipid Metabolism Pathway Alternations to Immunotherapy.

Tianli Cheng, Jing Zhang, Danni Liu, Guorong Lai, Xiaoping Wen.

  Immune checkpoint inhibitors (ICIs) significantly improve the survival of patients with non-small-cell lung cancer (NSCLC), but only some patients obtain clinical benefits. Predictive biomarkers for ICIs can accurately identify people who will benefit from immunotherapy. Lipid metabolism signaling plays a key role in the tumor microenvironment (TME) and immunotherapy. Hence, we aimed to explore the association between the mutation status of the lipid metabolism pathway and the prognosis of patients with NSCLC treated with ICIs. We downloaded the mutation data and clinical data of a cohort of patients with NSCLC who received ICIs. Univariate and multivariate Cox regression models were used to analyze the association between the mutation status of the lipid metabolism signaling and the prognosis of NSCLC receiving ICIs. Additionally, The Cancer Genome Atlas (TCGA)-NSCLC cohort was used to explore the relationships between the different mutation statuses of lipid metabolism pathways and the TME. Additionally, we found that patients with high numbers of mutations in the lipid metabolism pathway had significantly enriched macrophages (M0- and M1-type), CD4 + T cells (activated memory), CD8 + T cells, Tfh cells and gamma delta T cells, significantly increased expression of inflammatory genes [interferon-γ (IFNG), CD8A, GZMA, GZMB, CXCL9, and CXCL10] and enhanced immunogenic factors [neoantigen loads (NALs), tumor mutation burden (TMB), and DNA damage repair pathways]. In the local-NSCLC cohort, we found that the group with a high number of mutations had a significantly higher tumor mutation burden (TMB) and PD-L1 expression. High mutation status in the lipid metabolism pathway is associated with significantly prolonged progression-free survival (PFS) in NSCLC, indicating that this marker can be used as a predictive indicator for patients with NSCLC receiving ICIs.

Keywords:  immune checkpoint inhibitors; immune microenvironment; lipid metabolism pathway; non-small-cell lung cancer; predictive marker

DOI:  https://doi.org/10.3389/fgene.2021.646362
Pharmacology. 2021 Aug 05. 1-11

LncRNA XIST Contributes to Cisplatin Resistance of Lung Cancer Cells by Promoting Cellular Glycolysis through Sponging miR-101-3p.

Gang Hua, Zhao-Long Zeng, Yi-Ting Shi, Wei Chen, Li-Feng He, Guo-Fang Zhao.

   BACKGROUND: Non-small-cell lung carcinoma is one of the most frequently diagnosed cancers. Cisplatin (CDDP) is a currently applied standard anticancer agent for advanced lung cancers. Although effectively clinical response was achieved initially, a large fraction of lung cancer patients developed cisplatin resistance. Therefore, understanding the molecular mechanisms of chemoresistance is crucial for anti-lung cancer therapy. Long non-coding RNA (lncRNA)-X-inactive-specific transcript (XIST) has been reported to be positively associated with multiple cancers. Currently, the precise role and mechanism of XIST in cisplatin resistance of lung cancer have not been elucidated.
METHODS: The expression levels of miR-101-3p and lncRNA XIST were detected by qRT-PCR. Cisplatin-resistant lung cancer cell line was established by selecting the survival cells under gradually increased cisplatin treatments. The cell proliferation was detected by MTT assay, and the cellular glucose metabolism rate was evaluated by Seahorse metabolic flux analysis and glucose uptake and lactate product assays. Glycolysis-related protein expression levels were detected by Western blot. Dual luciferase reporter was constructed to determine the lncRNA-miRNA interaction.
RESULTS: Here, we report XIST is significantly upregulated in lung cancer tissues compared with normal lung tissues. In addition, cisplatin-resistant lung cancer cells displayed remarkably elevated XIST expression. We demonstrated that miR-101-3p functioned as a tumor suppressor in lung cancer and sensitized lung cancer cells to cisplatin. Bioinformatics analysis predicted miR-101-3p could be a potential target of XIST through direct binding with it as a competing endogenous RNA, which was further validated from lung tumor tissues and cell lines by luciferase assay. Intriguingly, XIST significantly promoted cellular glycolysis rate of lung cancer cells. The extracellular acidification rate, glucose uptake, and lactate product were elevated by XIST overexpression. On the contrary, miR-101-3p effectively suppressed glycolysis rate. Finally, we demonstrated silencing XIST significantly recovered miR-101-3p expression and downregulated expression of glycolysis key enzymes, a phenotype could be further overridden by miR-101-3p inhibition.
CONCLUSIONS: This study reveals a new molecular mechanism for the lncRNA-XIST-promoted cisplatin resistance via sponging miR-101-3p, leading to de-repression of cellular glycolysis. Moreover, these findings warrant further in vivo investigations to study XIST as a potential target to overcome cisplatin resistance.

Keywords:  Cisplatin resistance; Long non-coding RNA-X-inactive-specific transcript; Lung cancer; Warburg effect; miR-101-3p

DOI:  https://doi.org/10.1159/000512621
Invest New Drugs. 2021 Aug 02.

Preliminary evaluation of anticancer efficacy of pioglitazone combined with celecoxib for the treatment of non-small cell lung cancer.

Ammu V V V Ravi Kiran, Garikapati Kusuma Kumari, Praveen T Krishnamurthy.

   PURPOSE: Among the lung cancer types, non-small cell lung cancer (NSCLC) is prominent and less responsive to chemotherapy. The current chemotherapeutics for NSCLC are associated with several dose-limiting side effects like bone-marrow suppression, neurotoxicity, nephrotoxicity, and ototoxicity, etc. which are causing non-compliance in patients. Many tumors, including breasts, lung, ovarian, etc. overexpress PPAR-γ receptors and COX-2 enzymes, which play a crucial role in tumor progression, angiogenesis, and metastasis. Lack of PPAR-γ activation and overproduction of prostaglandins, result in uncontrolled activation of Ras/Raf/Mek ultimately, NF-κB mediated tumor proliferation. This study aimed to investigate the anti-cancer potential of PPAR-γ agonist Pioglitazone combined with COX-2 inhibitor Celelcoxib in NSCLC.
METHODS: Sixty adult Balb/C male mice were classified into sham control, disease control, and treatment groups. Mice were treated with Nicotine-derived nitrosamine ketone (NNK) (10 mg/kg), pioglitazone (10 & 20 mg/kg) and celecoxib (25 & 50 mg/kg). Weekly body weight, food intake, mean survival time & % increased life span were determined. Tumor weight and histopathological analysis were performed at the end of the study.
RESULTS: The significant tumor reducing potential of pioglitazone combined with celecoxib was observed (p < 0.05). The treatment groups (treated with pioglitazone and celecoxib) showed a remarkable decrease in lung tumor weight, improved life span and mean survival time (p < 0.05). Histopathological studies confirm that treatment groups (treated with pioglitazone and celecoxib) reframed the lung architecture compared to disease control.
CONCLUSION: Preliminary results revealed that pioglitazone adjunacy with celecoxib may be an effective chemo-preventive agent against NNK induce NSCLC.

Keywords:  Celecoxib; Lung tumorigenesis; Mice; Non-small cell lung cancer; Pioglitazone

DOI:  https://doi.org/10.1007/s10637-021-01158-7
J Proteome Res. 2021 Aug 03.

High-Throughput Salivary Metabolite Profiling on an Ultralow Noise Tip-Enhanced Laser Desorption Ionization Mass Spectrometry Platform for Noninvasive Diagnosis of Early Lung Cancer.

Xinrong Jiang, Xiaoming Chen, Zhao Chen, Jiekai Yu, Haizhou Lou, Jianmin Wu.

  Lung cancer (LC) is a widespread cancer that is the cause of the highest mortality rate accounting for 25% of all cancer deaths. To date, most LC patients are diagnosed at the advanced stage owing to the lack of obvious symptoms in the early stage and the limitations of current clinical diagnostic techniques. Therefore, developing a high throughput technique for early screening is of great importance. In this work, we established an effective and rapid salivary metabolic analysis platform for early LC diagnosis and combined metabolomics and transcriptomics to reveal the metabolic fluctuations correlated to LC. Saliva samples were collected from a total of 150 volunteers including 89 patients with early LC, 11 patients with advanced LC, and 50 healthy controls. The metabolic profiling of noninvasive samples was investigated on an ultralow noise TELDI-MS platform. In addition, data normalization methods were screened and assessed to overcome the MS signal variation caused by individual difference for biomarker mining. For untargeted metabolic profiling of saliva samples, around 264 peaks could be reliably detected in each sample. After multivariate analysis, 23 metabolites were sorted out and verified to be related to the dysfunction of the amino acid and nucleotide metabolism in early LC. Notably, transcriptomic data from online TCGA repository were utilized to support findings from the salivary metabolomics experiment, including the disorder of amino acid biosynthesis and amino acid metabolism. Based on the verified differential metabolites, early LC patients could be clearly distinguished from healthy controls with a sensitivity of 97.2% and a specificity of 92%. The ultralow noise TELDI-MS platform displayed satisfactory ability to explore salivary metabolite information and discover potential biomarkers that may help develop a noninvasive screening tool for early LC.

Keywords:  high-throughput; lung cancer; noninvasive diagnosis; salivary metabolomics

DOI:  https://doi.org/10.1021/acs.jproteome.1c00310
Anat Rec (Hoboken). 2021 Aug 04.

Screening and identification of potential novel lipid biomarkers for non-small cell lung cancer using UPLC-MS / MS.

Yu-Shuai Han, Li-Ying Shi, Jia-Xi Chen, Jing Chen, Zhi-Bin Li, Qi-Qi Lu, Shan-Qiang Zhang, Jun Liu, Wen-Jing Yi, Ting-Ting Jiang, Ji-Cheng Li, Jian Huang.

  Lung cancer is characterized by a high incidence rate and low survival rate. It is important to achieve early diagnosis of the disease. We applied ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS / MS) to screen plasma lipid spectrum in non-small cell lung cancer (NSCLC) patients, healthy controls (HC), and community-acquired pneumonia (CAP) patients. Modeling employing orthogonal partial least squares-discriminant analysis (OPLS-DA) combined with t-test was used to screen the differential lipids. Logistic regression analysis was used to establish the diagnostic model, while the accuracy was verified by 10-fold cross-validation. The results showed that the abnormal metabolism of lipid in NSCLC mainly comprised fatty acid metabolism, phospholipid metabolism, and glyceride metabolism. Four potential biomarkers, including LPC (14:0/0:0), LPI (14:1/0:0), DG (14:0/18:2/0:0) and LPC (16:1/0:0), were fitted by the receiver operating characteristic (ROC) curve model with the area under curve (AUC) value of 0.856, and the specificity and sensitivity were 87.0% and 78.0%, respectively. The results of cross validation showed that the AUC value of the model was 0.812, the sensitivity was 72.9%, and the specificity was 82.6%. The positive rate of four potential lipid biomarkers in this study (> 60.0%) was higher than that of existing tumor biomarkers in the clinical application. We investigated the plasma lipid profile of NSCLC patients and identified lipid biomarkers with potential diagnostic values. From the lipidomics perspective, our study may lay a foundation for the biomarker-based early diagnosis of lung cancer.

Keywords:  NSCLC; UPLC-MS/MS; lipids; plasma; potential biomarkers

DOI:  https://doi.org/10.1002/ar.24725
Cancer Metab. 2021 Aug 03. 9(1): 28

The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer.

Alexandra Giatromanolaki, Adrian L Harris, Michael I Koukourakis.

   BACKGROUND: Arginine (Arg) is essential for cancer cell growth and also for the activation of T cells. Thus, therapies aiming to reduce Arg utilization by cancer may prove detrimental for the immune response.
METHODS: We examined the expression of two major enzymes involved in arginine depletion and replenishment, namely arginase ARG2 and argininosuccinate synthase ASS1, respectively, in a series of 98 NSCLCs. Their association with immune infiltrates and the postoperative outcome were also studied.
RESULTS: ARG2 was expressed mainly by cancer-associated fibroblasts (CAFs) (58/98 cases; 59.2%), while ASS1 by cancer cells (75/98 cases; 76.5%). ASS1 and ARG2 expression patterns were not related to hypoxia markers. Auxotrophy, implied by the lack of expression of ASS1 in cancer cells, was associated with high angiogenesis (p < 0.02). ASS1 expression by cancer cells was associated with a high density of iNOS-expressing tumor-infiltrating lymphocytes (iNOS+TILs). ARG2 expression by CAFs was inversely related to the TIL-density and linked with poorer prognosis (p = 0.02). Patients with ASS1 expression by cancer cells had a better prognosis especially when CAFs did not express ARG2 (p = 0.004).
CONCLUSIONS: ARG2 and ASS1 enzymes are extensively expressed in NSCLC stroma and cancer cells, respectively. Auxotrophic tumors have a poor prognosis, potentially by utilizing Arg, thus reducing Arg-dependent TIL anti-tumor activity. ASS1 expression in cancer cells would allow Arg fueling of iNOS+TILs and enhance anti-tumor immunity. However, upregulation of ARG2 in CAFs may divert Arg from TILs, allowing immune escape. Identification of these three distinct phenotypes may be useful in the individualization of Arg-targeting therapies and immunotherapy.

Keywords:  ARG2; ASS1; Angiogenesis; Arginase; Arginine; Argininosuccinate synthase; Lung cancer; TILs

DOI:  https://doi.org/10.1186/s40170-021-00264-7
Oncol Lett. 2021 Sep;22(3): 671

Angiogenic activities are increased via upregulation of HIF-1α expression in gefitinib-resistant non-small cell lung carcinoma cells.

Jeong Eun Cha, Woom-Yee Bae, Jae-Sun Choi, Seung Hyeun Lee, Joo-Won Jeong.

  Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been used to treat patients with non-small cell lung cancer (NSCLC) and activating EGFR mutations; however, the emergence of secondary mutations in EGFR or the acquisition of resistance to EGFR-TKIs can develop and is involved in clinical failure. Since angiogenesis is associated with tumor progression and the blockade of antitumor drugs, inhibition of angiogenesis could be a rational strategy for developing anticancer drugs combined with EGFR-TKIs to treat patients with NSCLC. The signaling pathway mediated by hypoxia-inducible factor-1 (HIF-1) is essential for tumor angiogenesis. The present study aimed to identify the dependence of gefitinib resistance on HIF-1α activity using angiogenesis assays, western blot analysis, colony formation assay, xenograft tumor mouse model and immunohistochemical analysis of tumor tissues. In the NSCLC cell lines, HIF-1α protein expression levels and hypoxia-induced angiogenic activities were found to be increased. In a xenograft mouse tumor model, tumor tissues derived from gefitinib-resistant PC9 cells showed increased protein expression of HIF-1α and angiogenesis within the tumors. Furthermore, inhibition of HIF-1α suppressed resistance to gefitinib, whereas overexpression of HIF-1α increased resistance to gefitinib. The results from the present study provides evidence that HIF-1α was associated with the acquisition of resistance to gefitinib and suggested that inhibiting HIF-1α alleviated gefitinib resistance in NSCLC cell lines.

Keywords:  EGFR-TKIs; HIF-1α; NSCLC; angiogenesis; gefitinib

DOI:  https://doi.org/10.3892/ol.2021.12932