bims-meluca 2022-08-21 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–08–21
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

The aberrant cancer metabolic gene carbohydrate sulfotransferase 11 promotes non-small cell lung cancer cell metastasis via dysregulation of ceruloplasmin and intracellular iron balance.
PARP1 inhibition elicits immune responses against non-small cell lung cancer.
Increased glucose influx and glycogenesis in lung cancer cells surviving after irradiation.
Glutathione peroxidase 8 expression on cancer cells and cancer-associated fibroblasts facilitates lung cancer metastasis.
GNPNAT1 Predicts Poor Prognosis and Cancer Development in Non-Small Cell Lung Cancer.
Aspirin blocks AMPK/SIRT3-mediated glycolysis to inhibit NSCLC cell proliferation.
FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma.
Development and validation of endoplasmic reticulum stress-related eight-gene signature for predicting the overall survival of lung adenocarcinoma.

Transl Oncol. 2022 Aug 16. pii: S1936-5233(22)00167-X. [Epub ahead of print]25 101508

The aberrant cancer metabolic gene carbohydrate sulfotransferase 11 promotes non-small cell lung cancer cell metastasis via dysregulation of ceruloplasmin and intracellular iron balance.

Wei-Min Chang, Li-Jie Li, I-An Chiu, Tsung-Ching Lai, Yu-Chan Chang, Hsing-Fang Tsai, Chih-Jen Yang, Ming-Shyan Huang, Chia-Yi Su, Ting-Lun Lai, Yi-Hua Jan, Michael Hsiao.

  Aberrant metabolism has been proposed as one of the emerging hallmarks of cancer. However, the interplay between metabolic disorders and cancer metastasis remains to be defined. To explore the sophisticated metabolic processes during metastatic progression, we analyzed differentially expressed metabolic genes during the epithelial-mesenchymal transition (EMT) of lung cancer cells and defined the EMT-associated metabolic gene signature in lung adenocarcinoma patients. We found that the glycosaminoglycan (GAG)-chondroitin sulfate (CS) biosynthesis pathway was upregulated in the mesenchymal state of lung cancer and associated with poor prognosis. Notably, carbohydrate sulfotransferase 11 (CHST11), a crucial CS biosynthetic enzyme, was confirmed as a poor prognosis marker in non-small cell lung cancer (NSCLC) by immunohistochemical analysis. Moreover, forced CHST11 expression promoted invasion and metastasis, which was abolished by depleting the final product of CS biosynthesis by chondroitinase ABC treatment or active-domain negative CHST11. In vivo metastasis mouse models showed that CHST11 increased lung colonies number and sulfated mucosubstance expression. Furthermore, microarray analysis revealed ceruloplasmin (CP), which facilitated iron metabolism, was the downstream effector of CHST11. CP was upregulated by CHST11 through interferon-γ signaling pathway stimulation and related to unfavorable prognosis. Both forced CP expression and long-term iron treatment increased invasion and lung colony formation. Furthermore, we found 3-AP, an iron chelator, hampered the CHST11-induced metastasis. Our findings implicate that the novel CHST11-CP-iron axis enhances EMT and may serve as a new therapeutic target to treat NSCLC patients.

Keywords:  CHST11; EMT; Iron-metabolism; NSCLC

DOI:  https://doi.org/10.1016/j.tranon.2022.101508
Oncoimmunology. 2022 ;11(1): 2111915

PARP1 inhibition elicits immune responses against non-small cell lung cancer.

Pan Juncheng, Antoine Lafarge, Guido Kroemer, Maria Castedo.

  High levels of intracellular poly(ADP-ribose) (PAR) resulting from an elevated activity of PAR polymerase-1 (PARP1) correlate with poor infiltration of non-small cell lung cancers by cytotoxic T lymphocytes and dismal patient prognosis. Preclinical experimentation now demonstrates that PARP1 inhibition in cancer cells mediates strong immunostimulatory effects.

Keywords:  Anticancer immune response; immune escape; metabolism; non-small cell lung cancer; tumor microenvironment

DOI:  https://doi.org/10.1080/2162402X.2022.2111915
Int J Radiat Biol. 2022 Aug 17. 1-15

Increased glucose influx and glycogenesis in lung cancer cells surviving after irradiation.

Avgi Tsolou, Dimitrios Koparanis, Ioannis Lamprou, Alexandra Giatromanolaki, Michael I Koukourakis.

   PURPOSE: Lung cancer is considered as one of the most frequent malignancies worldwide. Radiotherapy is the main treatment modality applied for locally advanced disease, but remnant surviving cancer tissue results in disease progression in the majority of irradiated lung carcinomas. Metabolic reprogramming is regarded as a cancer hallmark and is associated with resistance to radiation therapy. Here, we explored metabolic alterations possibly related to cancer cell radioresistance.
MATERIALS AND METHODS: We compared the expression of metabolism-related enzymes in the parental A549 lung cancer cell line along with two new cell lines derived from A549 cells after recovery from three (A549-IR3) and six (A549-IR6) irradiation doses with 4Gy. Differential GLUT1 and GYS1 expression on proliferation and radioresistance were also comparatively investigated.
RESULTS: A549-IR cells displayed increased extracellular glucose absorption, and enhanced mRNA and protein levels of the GLUT1 glucose transporter. GLUT1 inhibition with BAY-876, suppressed cell proliferation and the effect was significantly more profound on A549-IR3 cells. Protein levels of molecules associated with aerobic or anaerobic glycolysis, or the phosphate pentose pathway were similar in all three cell lines. However, Glycogen Synthase 1 (GYS1) was upregulated, especially in the A549-IR3 cell line, suggestive of glycogen accumulation in cells surviving post irradiation. GYS1-gene silencing repressed the proliferation capacity of A549, but this increased their radioresistance. The radio-protective effect of the suppression of proliferative activity induced by GYS1 silencing did not protect A549-IR3 cells against further irradiation.
CONCLUSIONS: These findings indicate that GYS1 activity is a critical component of the metabolism of lung cancer cells surviving after fractionated radiotherapy. Targeting the glycogen metabolic reprogramming after irradiation may be a valuable approach to pursue eradication of the post-radiotherapy remnant of disease.

Keywords:  lung cancer; metabolic reprogramming; radioresistance; radiotherapy

DOI:  https://doi.org/10.1080/09553002.2022.2113837
MedComm (2020). 2022 Sep;3(3): e152

Glutathione peroxidase 8 expression on cancer cells and cancer-associated fibroblasts facilitates lung cancer metastasis.

Yu-Lian Xu, Luo-Wei Yuan, Xiao-Ming Jiang, Min-Xia Su, Mu-Yang Huang, Yu-Chi Chen, Le-Le Zhang, Xiuping Chen, Hong Zhu, Jin-Jian Lu.

  Lung cancer is the leading cause of cancer death worldwide, of which lung adenocarcinoma (LUAD) is the most common subtype. Metastasis is the major cause of poor prognosis and mortality for lung cancer patients, which urgently needs great efforts to be further explored. Herein, glutathione peroxidase 8 (GPX8) was identified as a novel potential pro-metastatic gene in LUAD metastatic mice models from GEO database. GPX8 was highly expressed in tumor tissues, predicting poor prognosis in LUAD patients. Knockdown of GPX8 inhibited LUAD metastasis in vitro and in vivo, while it did not obviously affect tumor growth. Knockdown of GPX8 decreased the levels of p-FAK and p-Paxillin and disturbed the distribution of focal adhesion. Furthermore, GPX8 was overexpressed in cancer-associated fibroblast (CAF) and associated with CAF infiltration in tumor microenvironment of lung cancer. GPX8 silence on fibroblasts suppressed lung cancer cell migration in the coculture system. BRD2 and RRD4 were the potential transcriptionally regulators for GPX8. Bromodomain extra-terminal inhibitor JQ1 downregulated GPX8 expression and suppressed lung cancer cell migration. Our findings indicate that highly expressed GPX8 in lung cancer cells and fibroblasts functions as a pro-metastatic factor in lung cancer. JQ1 is identified as a potential inhibitor against GPX8-mediated lung cancer metastasis.

Keywords:  CAF; GPX8; focal adhesion; lung cancer; metastasis

DOI:  https://doi.org/10.1002/mco2.152
Cancer Manag Res. 2022 ;14 2419-2428

GNPNAT1 Predicts Poor Prognosis and Cancer Development in Non-Small Cell Lung Cancer.

Yong Feng, Na Li, Yi Ren.

   Background: Glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is a key enzyme in the biosynthetic pathway of uridine diphosphate-N-acetylglucosamine and is upregulated in multiple malignancies. However, its function in cancer biology remains unclear.
Methods: Using TCGA dataset, this study analysed GNPNAT1 expression in non-small cell lung cancer (NSCLC) and assessed the correlation between GNPNAT1 and NSCLC patient prognosis. MTT and transwell assays were performed to determine the effect of GNPNAT1 on the growth and metastatic ability of lung cancer cells. GNPNAT1 expression was detected using immunohistochemistry in 78 NSCLC patients, and we analysed the correlation among clinicopathological parameters, overall survival (OS) and GNPNAT1 levels. Transcription factors that potentially regulate GNPNAT1 were explored using database analysis. RNF2 expression was verified using immunohistochemistry in NSCLC tissues.
Results: The results indicated that GNPNAT1 was upregulated in NSCLC, and patients with high GNPNAT1 levels had a poor prognosis. GNPNAT1 overexpression promoted the proliferative and metastatic ability of lung cancer cells, whereas GNPNAT1 knockdown showed the opposite effect. GNPNAT1 expression was upregulated in NSCLC tissues compared to matched normal tissues as assessed by immunohistochemistry. Moreover, GNPNAT1 levels were positively correlated with histological type and pathological stage. The negative correlation between GNPNAT1 levels and OS was confirmed in 78 NSCLC patients. Aberrant RNF2 partly contributed to the upregulation of GNPNAT1 expression in NSCLC.
Conclusion: These findings suggested that GNPNAT1 was upregulated and played an important role in NSCLC. GNPNAT1 is expected to represent an effective prognostic biomarker for NSCLC patients.

Keywords:  glucosamine-phosphate N-acetyltransferase 1; metastasis; non-small cell lung cancer; overall survival; proliferation

DOI:  https://doi.org/10.2147/CMAR.S367857
Eur J Pharmacol. 2022 Aug 15. pii: S0014-2999(22)00469-1. [Epub ahead of print] 175208

Aspirin blocks AMPK/SIRT3-mediated glycolysis to inhibit NSCLC cell proliferation.

Guanghui Ren, Yan Ma, Xingjie Wang, Zhaodi Zheng, Guorong Li.

  Non-small cell lung cancer (NSCLC) has the highest incidence and mortality in the world. Aspirin has been reported to promote apoptosis, inhibit proliferation, stemness, angiogenesis, cancer-associated inflammation and migration in NSCLC. But the effect of aspirin on aerobic glycolysis in NSCLC is less reported. In the present study, we investigated whether aspirin blocked aerobic glycolysis of NSCLC cell to inhibit proliferation. Our results showed that aspirin inhibited viability, PCNA expression, ability of colony formation, and reduced level of two glycolysis products, pyruvic acid and lactic acid, accompanied with reduced mitochondrial membrane potential (MMP), PGC-1α expression and ROS production to induce mitochondrial dysfunction in NSCLC cells. AMPK and mitochondrial-localized deacetylase sirtuin3 (SIRT3) were identified as the relevant molecular targets in glycolysis, but function mechanism and relationship between AMPK and SIRT3 for aspirin induced glycolysis inhibition remain unknown in cancer cells. The investigation of underlying mechanisms here indicated that aspirin activated AMPK pathway in dose- and time-dependent manners to inhibit aerobic glycolysis and proliferation by upregulating SIRT3 after application of compound C (CC), an inhibitor of AMPK activity or SIRT3 siRNA. Upon activation of SIRT3, aspirin promoted the release of hexokinase-II (HK-II) from mitochondria outer membrane to cytosol by deacetylating cyclophilin D (CypD). Consistently, aspirin significantly inhibited the growth of NSCLC xenografts and exhibited antitumor activity probably through AMPK/SIRT3/HK-II pathway in vivo. Collectively, AMPK/SIRT3/HK-II pathway plays a critical role in anticancer effects of aspirin, and our findings might serve as potential target for clinical practice and chemoprevention of aspirin in NSCLC.

Keywords:  AMPK; Aerobic glycolysis; Aspirin; Non-small cell lung cancer; Proliferation; SIRT3

DOI:  https://doi.org/10.1016/j.ejphar.2022.175208
Cell Death Dis. 2022 Aug 16. 13(8): 711

FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma.

Junjun Li, Yongchang Zhang, Li Wang, Min Li, Jianbo Yang, Pan Chen, Jie Zhu, Xiayu Li, Zhaoyang Zeng, Guiyuan Li, Wei Xiong, James B McCarthy, Bo Xiang, Mei Yi.

Lung cancer remains one of the most common malignancies and the leading cause of cancer-related death worldwide. Forkhead box protein A1 (FOXA1) is a pioneer factor amplified in lung adenocarcinoma (LUAD). However, its role in LUAD remains elusive. In this study, we found that expression of FOXA1 enhanced LUAD cell survival in nutrients deprived conditions through inhibiting autophagic cell death (ACD). FOXA1 bound to the imprinting control region of insulin-like growth factor 2 (IGF2) and interacted with DNA methyltransferase 1 (DNMT1), leading to initiation of DNMT1-mediated loss of imprinting (LOI) of IGF2 and autocrine of IGF2. Blockage of IGF2 and its downstream insulin-like growth factor 1 receptor (IGF1R) abolished the protective effect of FOXA1 on LUAD cells in nutrients deprived conditions. Furthermore, FOXA1 suppressed the expression of the lysosomal enzyme glucocerebrosidase 1 (GBA1), a positive mediator of ACD, through ubiquitination of GBA1 enhanced by IGF2. Notably, FOXA1 expression in A549 cells reduced the efficacy of the anti-angiogenic drug nintedanib to inhibit xenograft tumor growth, whereas a combination of nintedanib with IGF1R inhibitor linsitinib or mTORC1 inhibitor rapamycin enhanced tumor control. Clinically, high expression level of FOXA1 protein was associated with unfavorable prognosis in LUAD patients of advanced stage who received bevacizumab treatment. Our findings uncovered a previously unrecognized role of FOXA1 in mediating loss of imprinting of IGF2, which confer LUAD cells enhanced survival ability against nutrients deprivation through suppressing autophagic cell death.

DOI: https://doi.org/10.1038/s41419-022-05150-8
Transl Cancer Res. 2022 Jul;11(7): 1909-1924

Development and validation of endoplasmic reticulum stress-related eight-gene signature for predicting the overall survival of lung adenocarcinoma.

Lin Lin, Wei Zhang.

   Background: The high case-fatality rate of patients with lung adenocarcinoma (LUAD) emphasizes the importance of identifying a robust and reliable prognostic signature for LUAD patients. Endoplasmic reticulum (ER) stress results from protein misfolding imbalance and has been shown to participate in the development of cancer. We aimed to develop and validation a reliable and robust ER stress-related prognostic signature to accurately predict prognosis for patients with LUAD.
Methods: The mRNA expressions data and the clinical information were downloaded from The Cancer Genome Atlas (TCGA) as training set. The data of external validation sets were downloaded from GEO database with the accession number GSE 30219, GSE 31210, GSE 50081 and GSE 37745. Univariate Cox regression analyses was performed to identify mRNAs associated with overall survival (OS) in LUAD. ER-associated genes were retrieved using GeneCards database. Next, we construct the best risk score model by the least absolute shrinkage and selection operator (LASSO) regression with tenfold cross-validation. Subsequently, predictive models and risk scores were developed in the TCGA training dataset. Cox proportional hazards regression models were used for univariate and multivariate analysis of risk score and clinicopathologic characteristics. As a validation set GSE30219, GSE31210 and (GSE50081+GSE37745) were used to validate the predictive performance of the model in TCGA. Finally, functional enrichment analysis, including the gene ontology (GO) enrichment analysis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways and gene set enrichment analysis (GSEA) were performed to further explore function and mechanisms.
Results: A prognostic prediction model based on eight genes was developed in the TCGA training dataset. As expected, in validation sets, patients with higher risk scores were found to have worse prognosis. Time-dependent ROC curve analyses demonstrated that the risk score model was reliable. The nomograms showed excellent predictive ability. Multivariate Cox regression analyses indicated that the risk score was an independent prognostic factor for LUAD. Additionally, functional enrichment analysis showed that the relevant biomarkers were enriched in cell cycle and glycolysis related signaling pathways.
Conclusions: The 8-gene signature may enable improved the prediction of clinical events and decisions about management of LUAD.

Keywords:  Lung adenocarcinoma (LUAD); endoplasmic reticulum (ER) stress; overall survival (OS); prognostic signature; risk score

DOI:  https://doi.org/10.21037/tcr-22-106