bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2024–01–28
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice.
  2. IL-37 inhibits glycolysis of lung adenocarcinoma by inhibiting the expression of PFKFB3.
  3. Acetyltransferase P300 Regulates Glucose Metabolic Reprogramming through Catalyzing Succinylation in Lung Cancer.
  4. Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC.
  5. Traversing through the Mechanistic Event Analysis in IL-6 and IL-17 Signaling for a New Therapeutic Paradigm in NSCLC.
  6. Prognostic significance of integrating total metabolic tumor volume and EGFR mutation status in patients with lung adenocarcinoma.
  7. Hypoxia Modulates Radiosensitivity and Response to Different Radiation Qualities in A549 Non-Small Cell Lung Cancer (NSCLC) Cells.
  8. Prognostic Significance of Glycolysis-Related Genes in Lung Squamous Cell Carcinoma.
  9. The Addition of Atezolizumab to Chemotherapy in Non-Small Cell Lung Cancer: A Trial-Based Review and Meta-Analysis.
  1. Nat Commun. 2024 Jan 20. 15(1): 627
    Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice.
    Xue Yang, Jianming Wang, Chun-Yuan Chang, Fan Zhou, Juan Liu, Huiting Xu, Maria Ibrahim, Maria Gomez, Grace L Guo, Hao Liu, Wei-Xing Zong, Fredric E Wondisford, Xiaoyang Su, Eileen White, Zhaohui Feng, Wenwei Hu.
      Cancer cachexia is a systemic metabolic syndrome characterized by involuntary weight loss, and muscle and adipose tissue wasting. Mechanisms underlying cachexia remain poorly understood. Leukemia inhibitory factor (LIF), a multi-functional cytokine, has been suggested as a cachexia-inducing factor. In a transgenic mouse model with conditional LIF expression, systemic elevation of LIF induces cachexia. LIF overexpression decreases de novo lipogenesis and disrupts lipid homeostasis in the liver. Liver-specific LIF receptor knockout attenuates LIF-induced cachexia, suggesting that LIF-induced functional changes in the liver contribute to cachexia. Mechanistically, LIF overexpression activates STAT3 to downregulate PPARα, a master regulator of lipid metabolism, leading to the downregulation of a group of PPARα target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPARα by fenofibrate, a PPARα agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. These results provide valuable insights into cachexia, which may help develop strategies to treat cancer cachexia.
    DOI:  https://doi.org/10.1038/s41467-024-44924-w
  2. Cell Mol Biol (Noisy-le-grand). 2023 Dec 31. 69(15): 265-269
    IL-37 inhibits glycolysis of lung adenocarcinoma by inhibiting the expression of PFKFB3.
    Chunwang Liu, Rui Peng, Zonglong Nie, Li Zhao, Mingxue Zhu, Xiaofeng Mu.
      Aerobic glycolysis is one of the hallmarks of cancer. The metabolic phenotype of tumor cells is characterized by preferential dependence on glycolysis under aerobic conditions. Recent researchers have provided a piece of information on the effectiveness of targeting glycolysis. Thus, targeted glucose metabolism therapy is still a research hotspot. Interleukin 37 (IL-37) plays an important role in tumor development. Previous studies have found that IL-37 can inhibit the progression of lung adenocarcinoma in a variety of ways. For example, IL-37 can inhibit the migration and invasion of lung adenocarcinoma by inhibiting the interleukin 6(IL-6)/ Signal transducing activator of transcription 3(STAT3) pathway. IL-37 inhibits tumor growth by regulating RNA methylation at the M6A site of lung adenocarcinoma. It has been found that overexpression of IL-37 in macrophages can reverse the Warburg effect. The mechanism of IL-37 on glucose metabolism of tumor cells has not been studied. In research, glucose uptake and lactic acid production were inhibited in A549 cells with recombinant human IL-37(rhIL-37). Also, rhIL-37 inhibited the expression level of PFKFB3 in A549 cells. To verify whether the two aspects of rhIL-37's effects on A549 cells are related, we applied PFK15, a specific inhibitor of PFKFB3, to prove that rhIL-37 inhibits the glucose uptake and lactate production of A549 cells by inhibiting the expression of PFKFB3, and further inhibits the progression of lung adenocarcinoma.
    DOI:  https://doi.org/10.14715/cmb/2023.69.15.44
  3. Int J Mol Sci. 2024 Jan 15. pii: 1057. [Epub ahead of print]25(2):
    Acetyltransferase P300 Regulates Glucose Metabolic Reprogramming through Catalyzing Succinylation in Lung Cancer.
    Qingzhi Ma, Qingmei Zeng, Kun Wang, Meirui Qian, Jingzhuo Li, Hao Wang, Huijie Zhang, Jianli Jiang, Zhinan Chen, Wan Huang.
      Aberrant protein post-translational modification is a hallmark of malignant tumors. Lysine succinylation (Ksucc) plays a vital role in cell energy metabolism in various cancers. However, whether succinylation can be catalyzed by acetyltransferase p300 remains unclear. In this study, we unveiled that p300 is a "writer" for succinylation, and p300-mediated Ksucc promotes cell glycometabolism in lung adenocarcinoma (LUAD). Specifically, our succinylome data revealed that EP300 deficiency leads to the systemic reduction of Ksucc, and 79.55% of the p300-succinylated proteins were found in the cytoplasm, which were primarily enriched in the carbohydrate metabolism process. Interestingly, deleting EP300 led to a notable decrease in Ksucc levels on several glycolytic enzymes, especially Phosphoglycerate Kinase 1 (PGK1). Mutation of the succinylated site of PGK1 notably hindered cell glycolysis and lactic acid excretion. Metabolomics in vivo indicated that p300-caused metabolic reprogramming was mainly attributed to the altered carbohydrate metabolism. In addition, 89.35% of LUAD patients exhibited cytoplasmic localization of p300, with higher levels in tumor tissues than adjacent normal tissues. High levels of p300 correlated with advanced tumor stages and poor prognosis of LUAD patients. Briefly, we disclose the activity of p300 to catalyze succinylation, which contributes to cell glucose metabolic reprogramming and malignant progression of lung cancer.
    Keywords:  EP300; PGK1; glucose metabolism; lung cancer; lysine succinylation
    DOI:  https://doi.org/10.3390/ijms25021057
  4. BMC Cancer. 2024 Jan 24. 24(1): 123
    Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC.
    Jin-Sheng Liu, Yu-Xiang Cai, Yong-Ze He, Jian Xu, Su-Fang Tian, Zhi-Qiang Li.
       BACKGROUND: Brain metastasis is a common outcome in non-small cell lung cancer, and despite aggressive treatment, its clinical outcome is still frustrating. In recent years, immunotherapy has been developing rapidly, however, its therapeutic outcomes for primary lung cancer and brain metastases are not the same, suggesting that there may be differences in the immune microenvironment of primary lung cancer and brain metastases, however, we currently know little about these differences.
    METHODS: Seventeen paired samples of NSCLC and their brain metastases and 45 other unpaired brain metastases samples were collected for the current study. Immunohistochemical staining was performed on all samples for the following markers: immune checkpoints CTLA-4, PD-1, PD-L1, B7-H3, B7-H4, IDO1, and EphA2; tumor-infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD20; tumor-associated microglia/macrophages (TAMs) CD68 and CD163; and tumor proliferation index Ki-67. The differences in expression of these markers were compared in 17 paired samples, and the effect of the expression level of these markers on the prognosis of patients was analyzed in lung adenocarcinoma brain metastases samples. Subsequently, multiplex immunofluorescence staining was performed in a typical lung-brain paired sample based on the aforementioned results. The multiplex immunofluorescence staining results revealed the difference in tumor immune microenvironment between primary NSCLC and brain metastases.
    RESULTS: In 17 paired lesions, the infiltration of CTLA-4+ (P = 0.461), PD-1+ (P = 0.106), CD3+ (P = 0.045), CD4+ (P = 0.037), CD8+ (P = 0.008), and CD20+ (P = 0.029) TILs in brain metastases were significantly decreased compared with primary tumors. No statistically significant difference was observed in the CD68 (P = 0.954) and CD163 (P = 0.654) TAM infiltration between primary NSCLC and paired brain metastases. In all the brain metastases lesions, the expression of PD-L1 is related to the time interval of brain metastases in NSCLC. In addition, the Cox proportional hazards regression models showed high expression of B7-H4 (hazard ratio [HR] = 3.276, 95% confidence interval [CI] 1.335-8.041, P = 0.010) and CD68 TAM infiltration (HR = 3.775, 95% CI 1.419-10.044, P = 0.008) were independent prognosis factors for lung adenocarcinoma brain metastases patients.
    CONCLUSIONS: Both temporal and spatial heterogeneity is present between the primary tumor and brain metastases of NCSLC. Brain metastases lesions exhibit a more immunosuppressive tumor immune microenvironment. B7-H4 and CD68+ TAMs may have potential therapeutic value for lung adenocarcinoma brain metastases patients.
    Keywords:  Brain metastases; Immune checkpoint; Immunotherapy; Non-small cell lung cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12885-024-11875-w
  5. Int J Mol Sci. 2024 Jan 19. pii: 1216. [Epub ahead of print]25(2):
    Traversing through the Mechanistic Event Analysis in IL-6 and IL-17 Signaling for a New Therapeutic Paradigm in NSCLC.
    Riya Khilwani, Shailza Singh.
      IL-6 and IL-17 are paradoxical cytokines that progress inflammatory states in chronic diseases, including cancer. In lung cancer, their role has been elucidated to favor cancer development by modulating signaling mechanisms critical to cellular growth. The intrinsic ability of these cytokines to influence macroautophagy is yet another reason to facilitate lung cancer. Here, we employed a systems immunology approach to discover the mechanistic role of these cytokines in cancer development. In a biological system, at later stages, the activation of NFkB stimulates immunosuppressive phenotypes to achieve tolerating effects in a transformed cell. We found that the upregulation of cytokines signaled M2 macrophages to modulate tumor responses through the activation of autophagic intermediates and inflammasome mediators. This caused immune perturbations in the tumor microenvironment, which were associated with cancer inflammation. To address these inflammatory states, we performed triggered event analysis to examine whether overexpressing immune effectors or downregulating immune suppressors may have an effect on cancer reversal. Interestingly, the inhibition of immune regulators opposed the model outcome to an increased immune response. Therefore, IL6-IL17-mediated regulation of lung cancer may address tumor malignancy and potentiate the development of newer therapeutics for NSCLC.
    Keywords:  IL-17; IL-6; M2 macrophages; NFkB; NSCLC; systems immunology
    DOI:  https://doi.org/10.3390/ijms25021216
  6. PeerJ. 2024 ;12 e16807
    Prognostic significance of integrating total metabolic tumor volume and EGFR mutation status in patients with lung adenocarcinoma.
    Maoqing Jiang, Xiuyu Guo, Ping Chen, Xiaohui Zhang, Qiaoling Gao, Jingfeng Zhang, Jianjun Zheng.
       Background: The objective of this study was to investigate the prognostic significance of total metabolic tumor volume (TMTV) derived from baseline 18F-2-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), in conjunction with epidermal growth factor receptor (EGFR) mutation status, among patients with lung adenocarcinoma (LUAD).
    Methods: We performed a retrospective analysis on 141 patients with LUAD (74 males, 67 females, median age 67 (range 34-86)) who underwent 18F-FDG PET/CT and had their EGFR mutation status determined. Optimal cutoff points for TMTV were determined using time-dependent receiver operating characteristic curve analysis. The survival difference was compared using Cox regression analysis and Kaplan‒Meier curves.
    Results: The EGFR mutant patients (n = 79, 56.0%) exhibited significantly higher 2-year progression-free survival (PFS) and overall survival (OS) rates compared to those with EGFR wild-type (n = 62, 44.0%), with rates of 74.2% vs 69.2% (P = 0.029) and 86.1% vs 67.7% (P = 0.009), respectively. The optimal cutoff values of TMTV were 36.42 cm3 for PFS and 37.51 cm3 for OS. Patients with high TMTV exhibited significantly inferior 2-year PFS and OS, with rates of 22.4% and 38.1%, respectively, compared to those with low TMTV, who had rates of 85.8% and 95.0% (both P < 0.001). In both the EGFR mutant and wild-type groups, patients exhibiting high TMTV demonstrated significantly inferior 2-year PFS and OS compared to those with low TMTV. In multivariate analysis, EGFR mutation status (hazard ratio, HR, 0.41, 95% confidence interval, CI [0.18-0.94], P = 0.034) and TMTV (HR 8.08, 95% CI [2.34-28.0], P < 0.001) were independent prognostic factors of OS, whereas TMTV was also an independent prognosticator of PFS (HR 2.59, 95% CI [1.30-5.13], P = 0.007).
    Conclusion: Our study demonstrates that the integration of TMTV on baseline 18F-FDG PET/CT with EGFR mutation status improves the accuracy of prognostic evaluation for patients with LUAD.
    Keywords:  18F-2-fluoro-2-deoxyglucose; Computed tomography; Epidermal growth factor receptor; Lung adenocarcinoma; Metabolic tumor volume; Positron emission tomography
    DOI:  https://doi.org/10.7717/peerj.16807
  7. Int J Mol Sci. 2024 Jan 13. pii: 1010. [Epub ahead of print]25(2):
    Hypoxia Modulates Radiosensitivity and Response to Different Radiation Qualities in A549 Non-Small Cell Lung Cancer (NSCLC) Cells.
    Hasan Nisar, Frederik M Labonté, Marie Denise Roggan, Claudia Schmitz, François Chevalier, Bikash Konda, Sebastian Diegeler, Christa Baumstark-Khan, Christine E Hellweg.
      Hypoxia-induced radioresistance reduces the efficacy of radiotherapy for solid malignancies, including non-small cell lung cancer (NSCLC). Cellular hypoxia can confer radioresistance through cellular and tumor micro-environment adaptations. Until recently, studies evaluating radioresistance secondary to hypoxia were designed to maintain cellular hypoxia only before and during irradiation, while any handling of post-irradiated cells was carried out in standard oxic conditions due to the unavailability of hypoxia workstations. This limited the possibility of simulating in vivo or clinical conditions in vitro. The presence of molecular oxygen is more important for the radiotoxicity of low-linear energy transfer (LET) radiation (e.g., X-rays) than that of high-LET carbon (12C) ions. The mechanisms responsible for 12C ions' potential to overcome hypoxia-induced radioresistance are currently not fully understood. Therefore, the radioresistance of hypoxic A549 NSCLC cells following exposure to X-rays or 12C ions was investigated along with cell cycle progression and gene expression by maintaining hypoxia before, during and after irradiation. A549 cells were incubated under normoxia (20% O2) or hypoxia (1% O2) for 48 h and then irradiated with X-rays (200 kV) or 12C ions (35 MeV/n, LET ~75 keV/µm). Cell survival was evaluated using colony-forming ability (CFA) assays immediately or 24 h after irradiation (late plating). DNA double-strand breaks (DSBs) were analyzed using γH2AX immunofluorescence microscopy. Cell cycle progression was determined by flow cytometry of 4',6-diamidino-2-phenylindole-stained cells. The global transcription profile post-irradiation was evaluated by RNA sequencing. When hypoxia was maintained before, during and after irradiation, hypoxia-induced radioresistance was observed only in late plating CFA experiments. The killing efficiency of 12C ions was much higher than that of X-rays. Cell survival under hypoxia was affected more strongly by the timepoint of plating in the case of X-rays compared to 12C ions. Cell cycle arrest following irradiation under hypoxia was less pronounced but more prolonged. DSB induction and resolution following irradiation were not significantly different under normoxia and hypoxia. Gene expression response to irradiation primarily comprised cell cycle regulation for both radiation qualities and oxygen conditions. Several PI3K target genes involved in cell migration and cell motility were differentially upregulated in hypoxic cells. Hypoxia-induced radioresistance may be linked to altered cell cycle response to irradiation and PI3K-mediated changes in cell motility and migration in A549 cells rather than less DNA damage or faster repair.
    Keywords:  NSCLC; PI3K responsive genes; cell cycle response; cellular hypoxia; colony forming ability; high-LET radiation; radiosensitivity
    DOI:  https://doi.org/10.3390/ijms25021010
  8. Int J Mol Sci. 2024 Jan 17. pii: 1143. [Epub ahead of print]25(2):
    Prognostic Significance of Glycolysis-Related Genes in Lung Squamous Cell Carcinoma.
    Sultan F Kadasah.
      Lung squamous cell carcinoma (LUSC) is one of the most common malignancies. There is growing evidence that glycolysis-related genes play a critical role in tumor development, maintenance, and therapeutic response by altering tumor metabolism and thereby influencing the tumor immune microenvironment. However, the overall impact of glycolysis-related genes on the prognostic significance, tumor microenvironment characteristics, and treatment outcome of patients with LUSC has not been fully elucidated. We used The Cancer Genome Atlas (TCGA) dataset to screen glycolysis-related genes with prognostic effects in LUSC and constructed signature and nomogram models using Lasso and Cox regression, respectively. In addition, we analyzed the immune infiltration and tumor mutation load of the genes in the models. We finally obtained a total of glycolysis-associated DEGs. The signature model and nomogram model had good prognostic power for LUSC. Gene expression in the models was highly correlated with multiple immune cells in LUSC. Through this analysis, we have identified and validated for the first time that glycolysis-related genes are highly associated with the development of LUSC. In addition, we constructed the signature model and nomogram model for clinical decision-making.
    Keywords:  glycolysis; lung squamous cell carcinoma; signature model
    DOI:  https://doi.org/10.3390/ijms25021143
  9. World J Oncol. 2024 Feb;15(1): 72-80
    The Addition of Atezolizumab to Chemotherapy in Non-Small Cell Lung Cancer: A Trial-Based Review and Meta-Analysis.
    Nadya Keumala Fitri, Bahagia Willibrordus Maria Nainggolan, Naufal Nandita Firsty, Andika Pradana, Dina Keumala Sari.
       Background: Non-small cell lung cancer (NSCLC) stands as one of the most prevalent types of cancer worldwide, driving extensive research in oncologic therapeutic approaches. Atezolizumab, among the treatments under scrutiny, is undergoing evaluation as a potential first-line therapy for NSCLC. This review aims to assess the efficacy of atezolizumab in treating patients with NSCLC and to shed light on the ongoing quest for the most effective treatment.
    Methods: Multiple scientific databases, including PubMed, Cochrane, and ScienceDirect, were consulted. The literature identification utilized the strategic Boolean term method of keywords relating to "non-small cell lung cancer" and "atezolizumab" to suggest the analyzed population in our review without restricting the potential outcomes. The primary inclusion criterion is clinical studies that attempted to determine the efficacy of atezolizumab in NSCLC patients.
    Results: We included four trials to be analyzed in the final analysis, which we stratified into the programmed cell death-ligand 1 (PD-L1) expressivity status aside from the pooled intention-to-treat (ITT) population. We found the addition of atezolizumab may significantly improve the overall survival (OS) in the respective arm, remarkably among the high PD-L1 expression group (TC3 or IC3). The result of our meta-analysis presented the pooled OS of 0.79 (0.72, 0.87) in 95% confidence interval (CI) with a P value of < 0.05. Sub-analysis of the PD-L1's expression revealed TC3 population benefits the most (hazard ratio (HR): 0.55, 95% CI (0.42, 0.73)), compared to low (HR: 0.80, 95% CI (0.68, 0.93)) and negative expression (HR: 0.79, 95% CI (0.68, 0.93)); which is statistically meaningful (P < 0.05). Similar result was also observed in progression-free survival (PFS) analysis with the HR value of 0.63 (0.55, 0.72), with P value of < 0.05, favoring atezolizumab arm.
    Conclusions: Upon examination, the study reveals that the addition of atezolizumab demonstrates notable improvements in both OS and PFS among NSCLC patients. These findings present promising attributes for atezolizumab as a viable treatment for NSCLC. However, it is important to acknowledge that the future holds further revelations in this realm, and more insights are yet to be uncovered.
    Keywords:  Atezolizumab; Chemotherapy; NSCLC; Overall survival; Progression-free survival
    DOI:  https://doi.org/10.14740/wjon1701
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