bims-meluca 2025-06-08 papers

Cell Biol Toxicol. 2025 May 31. 41(1): 94

Lipidomics reveals effect of EHHADH in lung squamous cell.

Jianan Huang, Linlin Zhang, Wanxin Duan, Liyang Li, Xiaoxia Liu, Xiangdong Wang.

Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are two major pathological types of non-small cell lung cancer (NSCLC), characterized by distinct patterns of lipid metabolism. However, the molecular mechanisms underlying lipid metabolism reprogramming specific to LUSC remain poorly understood. This study aims to fill this gap by identifying and characterizing EHHADH (enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase) as a key regulator of medium-chain fatty acid metabolism in LUSC. The peroxisomal L-bifunctional enzyme is one of the important elements to control the peroxisomal fatty acid beta-oxidation pathway. Through high-expression genes related to lipid metabolism were identified by data mining, the expression and regulatory effects of EHHADH in different cell lines were investigated. EHHADH was highly expressed in LUSC cells and exhibited different expression patterns from those in LUAD cells. Knockdown of EHHADH in LUSC cell lines led to a marked reduction in cell proliferation. RNA sequencing following EHHADH silencing demonstrated significant changes in the expression of lipid metabolism-related genes in different cell lines, such as AZGP1, CAV1, CYP3A4, NR2F2, NR3C2, and RARG. Lipidomics analysis further demonstrated that EHHADH plays a crucial role in regulating intracellular and extracellular lipid profiles. EHHADH knockdown resulted in increased levels of long-chain fatty acids and storage lipids, while decreased levels of medium-chain fatty acids. Conversely, overexpression of EHHADH reduced long-chain fatty acids and storage lipids, while increasing specific medium-chain fatty acids. These metabolic alterations were consistent with changes in lipid metabolism-related protein expression, supporting the molecular mechanistic role of EHHADH in lipid regulation. In conclusion, EHHADH functions as an important regulator of lipid metabolism in LUSC and plays a key role in the occurrence, progression, and treatment of lung cancer. The important impact of EHHADH in lipid metabolism disorders suggests potential utility as a biomarker for diagnosis and a target for personalized treatment strategies in lung cancer.

Keywords: EHHADH; Lipid metabolism; Lipidomics; Lung squamous carcinoma

DOI: https://doi.org/10.1007/s10565-025-10044-4

J Pharmacol Exp Ther. 2025 May 03. pii: S0022-3565(25)39811-3. [Epub ahead of print]392(6): 103598

Metabolic stress-mediated cell death and autophagy in human lung cancer cells.

Himani Joshi, Ying Huang, M Saeed Sheikh.

Lung cancer remains one of the major causes of cancer-related mortality. Thus, newer therapeutic approaches are urgently needed. Because cancer is a metabolic disease, lung cancer cells have also rewired their metabolism to gain growth advantage and support survival. Therefore, the use of metabolic stress-inducing agents as a therapeutic strategy for lung cancer is an attractive idea. In this study, we have investigated the anticancer potential of CB-839 and metformin. CB-839, a selective glutaminase-1 inhibitor, creates glutamine-deficient conditions, and metformin is an antidiabetic drug. We report that CB-839 and metformin induce metabolic stress and inhibit growth of human lung cancer cells. Of note, lung cancer cells that harbor mutant K-Ras are more sensitive to these agents compared to cells with wild-type K-Ras status. In the K-Ras mutant cells, these agents induce cell death partly, via death receptor 5 (DR5)-dependent extrinsic pathway. However, in the lung cancer cells harboring wild-type K-Ras, these agents activate autophagy without significant effect on DR5 regulation. Pretreatment of K-Ras wild-type cells with autophagy inhibitor improves the anticancer potential of these agents coupled with activation of DR5-dependent pathway. Our results further show that the growth inhibitory effects of these agents appear to be linked to the mutant K-Ras status because pan-K-Ras inhibitor that inhibits the mutant K-Ras proteins blunted the growth inhibitory effects of these agents in cells harboring mutant K-Ras. Collectively, our results provide valuable new insights into exploiting the metabolic rewiring of lung cancer cells by using metabolic stress-inducing drugs as an important therapeutic approach. SIGNIFICANCE STATEMENT: Anticancer potential of CB-839 and metformin is investigated in lung cancer. These agents induce cell death partly, via death receptor 5-dependent pathway, and a relationship with K-Ras status of lung cancer cells is noted. Lung cancer cells with mutant K-Ras are more sensitive compared to cells with wild-type K-Ras. Autophagy inhibition of K-Ras wild-type cells improves the anticancer potential. This study provides new insights into exploiting the metabolic rewiring of lung cancer cells as an important therapeutic strategy.

Keywords: Autophagy; CB-839; Cell death; Death receptor 5; Metabolic stress; Metformin

DOI: https://doi.org/10.1016/j.jpet.2025.103598

bioRxiv. 2025 May 20. pii: 2025.05.15.654370. [Epub ahead of print]

Sustained Glucose Turnover Flux Distinguishes Cancer Cachexia from Nutrient Limitation.

Young-Yon Kwon, Yanshan Liang, Maria Gomez-Jenkins, Mujmmail Ahmed, Guangru Jiang, Juliya Hsiang, David Y Lewis, Tobias Janowitz, Marcus D Goncalves, Eileen White, Sheng Hui.

Cancer cachexia is an involuntary weight loss condition characterized by systemic metabolic disorder. A comprehensive flux characterization of this condition however is lacking. Here, we systematically isotope traced eight major circulating nutrients in mice bearing cachectic C26 tumors (cxC26) and food intake-matched mice bearing non-cachectic C26 tumors (ncxC26). We found no difference in whole-body lipolysis and proteolysis, ketogenesis, or fatty acid and ketone oxidation by tissues between the two groups. In contrast, compared to ncxC26 mice ad libitum, glucose turnover flux decreased in food intake-controlled ncxC26 mice but not in cxC26 mice. Similarly, sustained glucose turnover flux was observed in two autochthonous cancer cachexia models despite reduced food intake. We identified glutamine and alanine as responsible for sustained glucose production and tissues with altered use of glucose and lactate in cxC26 mice. We provide a comprehensive view of metabolic alterations in cancer cachexia revealing those distinct from decreased nutrient intake.
Highlights: Quantitative fluxomics of cancer cachexia under matched food intake and body weightIntact lipolysis, proteolysis, ketogenesis, and lipid oxidation in cachectic miceSustained glucose consumption in cachectic mice despite reduced food intakeIncreased glucose production from glutamine and alanine in cachectic mice.

DOI: https://doi.org/10.1101/2025.05.15.654370

Discov Oncol. 2025 Jun 04. 16(1): 1005

Connection between circulating inflammatory cytokines and non-small cell lung cancer: integrated Mendelian randomization and gene function analysis.

Ke Niu, Jing Tang, Jianxin Zhong, Lin Zheng, Yayu Zhu, Huijuan Ling, Yu Liu, Qing Xu, Ping Qiu, Liwen Chen.

BACKGROUND: A lot of cancers including non-small cell lung cancer (NSCLC) arise in association with chronic inflammation. In this study, Mendelian randomization (MR) and gene function analyses were integrated to address the connection between circulating inflammatory cytokines and NSCLC, and the underlying biological processes and functional significance of the correlated inflammatory cytokines.
METHODS: We employed the summary statistics of 91 inflammatory cytokines and NSCLC from the genome-wide association studies. The bidirectional MR analysis was used to identify cytokines causally associated with NSCLC. The Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were used to explore the biological pathways and functional significance of the cytokines involved in the causal relationship. By using 1400 blood metabolites data and the two-step MR with an inverse variance weighted (IVW) approach, we assessed the extent to which the effect of cytokines on the risk of NSCLC was mediated by metabolites.
RESULTS: C-C motif chemokine ligand 11 (CCL11) (P = 0.008) and CCL2 (P = 0.026) were positively correlated with NSCLC, whereas TNF-related apoptosis inducing ligand (TRAIL) (P = 0.030) and signaling lymphocytic activation molecule family member 1 (SLAMF1) (P = 0.049) were negatively associated with NSCLC. Conversely, NSCLC led to an increase of CCL13 (P = 0.025) while stem cell factor (SCF) (P = 0.009), tumor necrosis factor beta (TNF-β) (P = 0.033), and interleukin-10 (IL-10) (P = 0.042) were downregulated in NSCLC. The KEGG analysis revealed that these eight cytokines were involved in 14 distinct pathways (all adjusted P < 0.05). The GO analysis showed enrichment of specific terms associated with these cytokines (all adjusted P < 0.05). The GSEA results indicated these eight cytokines were collectively enriched in 15 biological pathways. The top 5 pathways of the ranked list are Jak-STAT, PI3K-AKT, FAK-CDC42, RTK-PI3K and PLCG-Calcineurin signaling pathways (all P < 0.05 and false discovery rate < 0.25).The two-step MR analysis showed that 1-palmitoyl-2-linoleoyl-gpc (16:0/18:2) (PC(16:0/18:2(9Z,12Z))) (P = 3.87 × 10-5) mediates the connection between CCL2 and NSCLC, with mediated proportion of 19.4% (P = 0.039).
CONCLUSION: The circulating inflammatory cytokines CCL11, CCL2, CCL13 and IL-10 are predominantly correlated with NSCLC, and the Jak-STAT, PI3K-AKT, FAK-CDC42, RTK-PI3K and PLCG-Calcineurin signaling pathways are closely enriched in the connection. In addition, alteration in lipid metabolism, especially phosphatidylcholine (PC) metabolism is independently linked with the risk of NSCLC induced by inflammatory cytokines.

Keywords: Blood metabolites; Circulating inflammatory cytokines; Gene function analysis; Mendelian randomization; Non-small cell lung cancer

DOI: https://doi.org/10.1007/s12672-025-02817-4

BJR Open. 2025 Jan;7(1): tzaf010

The effects of anti-PD-1 therapy on programmed death-ligand 1 expression and glucose metabolism of normal organs in patients with advanced non-small cell lung cancer.

Matthew Severyn, Eunice H L Lee, Gitasha Chand, Jessica Johnson, Damion Bailey, Kathryn Adamson, Vicky Goh, Daniel Johnathan Hughes, Gary J R Cook.

Objectives: To investigate how anti-PD-1 treatment affects both Programmed Death-Ligand 1 (PD-L1) expression and glucose metabolism within normal tissues of advanced non-small cell lung cancer (NSCLC) patients using a dual SPECT/CT and PET/CT imaging approach.
Methods: Ten advanced NSCLC patients (NCT04436406) undergoing anti-PD-1 therapy ± chemotherapy underwent imaging at baseline and 9 weeks. PD-L1 expression was measured using [99mTc]-labelled single-domain PD-L1 antibody single-photon emission computed tomography/computed tomography ([99mTc]NM-01 SPECT/CT). Glucose uptake was measured using [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT). Two independent observers marked regions of interest across normal organs (liver, lung, spleen, bone marrow, muscle, kidney, pancreas, left ventricular myocardium, and blood pool) to determine maximum and mean standardized uptake values (SUV) at both time points. Observer agreement was measured with an intraclass correlation coefficient (ICC).
Results: No significant changes in SUVs, indicating PD-L1 expression and glucose metabolism, were detected in normal organs after 9 weeks of treatment (all P > .05). No patients developed immune-related adverse events (irAEs) during the study period. Observer measurements showed excellent consistency with an ICC of 0.99 (95% confidence interval 0.99-0.99).
Conclusions: Our study showed stable PD-L1 expression and glucose metabolism within normal organs in advanced NSCLC patients treated with anti-PD-1 therapy ± chemotherapy. Interobserver reliability between observers was excellent. Additional studies with larger patient groups and a specific focus on irAE cases are needed.
Advances in knowledge: Through a dual-modality molecular imaging approach, this research provides novel insight into anti-PD-1 therapy's effects on PD-L1 expression and glucose metabolism in normal organs of NSCLC patients, demonstrating that these parameters remain stable post-treatment.

Keywords: PET/CT imaging; [99mTc]NM-01; non-small cell lung cancer

DOI: https://doi.org/10.1093/bjro/tzaf010