bims-meluca 2024-02-04 papers

Front Biosci (Landmark Ed). 2024 Jan 18. 29(1): 27

KLF8 Promotes the Survival of Lung Adenocarcinoma During Nutrient Deprivation by Regulating the Pentose Phosphate Pathway through SIRT2.

Qiaohong Bai, Wenfang Jin, Futao Chen, Jiang Zhu, Lifeng Cao, Yang Yang, Fukuan Zhong, Li Li.

BACKGROUND: The pentose phosphate pathway (PPP) is a critical metabolic pathway that generates NADPH and ribose-5-phosphate for nucleotide biosynthesis and redox homeostasis. In this study, we investigated a potential regulatory role for Krüppel-like factor 8 (KLF8) in the control of PPP in lung adenocarcinoma (LUAD) cells.METHODS: Based on a comprehensive set of experimental approaches, including cell culture, molecular techniques, and functional assays, we revealed a novel mechanism by which KLF8 promotes the activation of glucose-6-phosphate dehydrogenase (G6PD), a component enzyme in the PPP.
RESULTS: Our findings demonstrate that KLF8 inhibits the acetylation of G6PD, leading to its increased enzymatic activity. Additionally, we observed that KLF8 activates the transcription of SIRT2, which has been implicated in regulating G6PD acetylation. These results highlight the interplay between KLF8, G6PD, and protein acetylation in the regulation of PPP in LUAD.
CONCLUSIONS: Understanding the intricate molecular mechanisms underlying the metabolic reprogramming driven by KLF8 in lung cancer provides valuable insights into potential therapeutic strategies targeting the PPP. This study emphasizes the significance of KLF8 as a key modulator of metabolic pathways and indicates the potential of targeting the KLF8-G6PD axis for lung cancer treatment.

Keywords: KLF8; nutrient deprivation; pentose phosphate pathway; tumor metabolism

DOI: https://doi.org/10.31083/j.fbl2901027

Oncol Lett. 2024 Mar;27(3): 110

Clinical impact of inflammatory and nutrition index based on metabolic tumor activity in non‑small cell lung cancer treated with immunotherapy.

Koki Ito, Kousuke Hashimoto, Kyoichi Kaira, Ou Yamaguchi, Atsuto Mouri, Ayako Shiono, Yu Miura, Kunihiko Kobayashi, Hisao Imai, Ichiei Kuji, Hiroshi Kagamu.

The aim of the present study was to explore the relationship between tumor metabolic glycolysis and inflammatory or nutritional status in patients with advanced non-small cell lung cancer (NSCLC) who received programmed death-1 (PD-1) blockade. A total of 186 patients were registered in the present study. All of patients underwent 18F-FDG PET imaging before initial PD-1 blockade, and maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed as indicators of 18F-FDG uptake. As inflammatory and nutritional index, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ration (PLR), systemic immune inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI) and Glasgow prognostic score (GPS) were evaluated based on previous assessment. 18F-FDG uptake by MTV and TLG significantly correlated with the scores of NLR, PLR, SII, PNI and ALI, in addition to the level of albumin, lactate dehydrogenase, C-reactive protein, white blood cells, neutrophils, lymphocytes and body mass index. The count of NLR, PLR and SII was significantly higher in patients with <1 year overall survival (OS) compared with in those with ≥1 year OS, and that of PNI and ALI was significantly lower in those with <1 year OS compared with those with ≥1 year OS. High MTV under the high PLR, SII and low ALI were identified as significant factors for predicting the decreased PFS and OS after PD-1 blockade in a first-line setting. In second or more lines, high MTV was identified as a significant prognostic predictor regardless of the levels of PLR, SII, ALI and GPS. In conclusion, metabolic tumor glycolysis determined by MTV was identified as a predictor for the outcome of PD-1 blockade under the high inflammatory and low nutritional conditions, in particular, when treated with a first-line PD-1 blockade. A high MTV under high PLR and SII and low ALI in the first-line setting could be more predictive of ICI treatment than other combinations.

Keywords: 18F-FDG; PET; immunotherapy; inflammatory; lung cancer; nutrition; programmed death-1

DOI: https://doi.org/10.3892/ol.2024.14243

Front Mol Biosci. 2023 ;10 1279645

Exploration of oxidized phosphocholine profile in non-small-cell lung cancer.

Joanna Godzien, Angeles Lopez-Lopez, Julia Sieminska, Kacper Jablonowski, Karolina Pietrowska, Joanna Kisluk, Malgorzata Mojsak, Zofia Dzieciol-Anikiej, Coral Barbas, Joanna Reszec, Miroslaw Kozlowski, Marcin Moniuszko, Adam Kretowski, Jacek Niklinski, Michal Ciborowski.

Introduction: Lung cancer is one of the most frequently studied types of cancer and represents the most common and lethal neoplasm. Our previous research on non-small cell lung cancer (NSCLC) has revealed deep lipid profile reprogramming and redox status disruption in cancer patients. Lung cell membranes are rich in phospholipids that are susceptible to oxidation, leading to the formation of bioactive oxidized phosphatidylcholines (oxPCs). Persistent and elevated levels of oxPCs have been shown to induce chronic inflammation, leading to detrimental effects. However, recent reports suggest that certain oxPCs possess anti-inflammatory, pro-survival, and endothelial barrier-protective properties. Thus, we aimed to measure the levels of oxPCs in NSCLC patients and investigate their potential role in lung cancer. Methods: To explore the oxPCs profiles in lung cancer, we performed in-depth, multi-level metabolomic analyses of nearly 350 plasma and lung tissue samples from 200 patients with NSCLC, including adenocarcinoma (ADC) and squamous cell carcinoma (SCC), the two most prevalent NSCLC subtypes and COPD patients as a control group. First, we performed oxPC profiling of plasma samples. Second, we analyzed tumor and non-cancerous lung tissues collected during the surgical removal of NSCLC tumors. Because of tumor tissue heterogeneity, subsequent analyses covered the surrounding healthy tissue and peripheral and central tumors. To assess whether the observed phenotypic changes in the patients were associated with measured oxPC levels, metabolomics data were augmented with data from medical records. Results: We observed a predominance of long-chain oxPCs in plasma samples and of short-chain oxPCs in tissue samples from patients with NSCLC. The highest concentration of oxPCs was observed in the central tumor region. ADC patients showed higher levels of oxPCs compared to the control group, than patients with SCC. Conclusion: The detrimental effects associated with the accumulation of short-chain oxPCs suggest that these molecules may have greater therapeutic utility than diagnostic value, especially given that elevated oxPC levels are a hallmark of multiple types of cancer.

Keywords: NSCLC; epilipidomics; lung cancer; oxPC; oxidized phospholipids

DOI: https://doi.org/10.3389/fmolb.2023.1279645

Antioxid Redox Signal. 2024 Feb 01.

Activation of HIF-1α-mediated DNA methylation enzymes (DNMT3a and TET2) under hypoxic conditions regulates S100A6 transcription to promote lung cancer cell growth and metastasis.

Tengfei Wang, Genbao Zhu, Bo Wang, Mengxue Hu, Chen Gong, Kemeng Tan, La Jiang, Xiaohong Zhu, Yuliu Geng, Lili Li.

AIM: This research was aimed at investigating the effects of HIF-1α-mediated DNA methylation enzymes (TET2 and DNMT3a) under hypoxic conditions on S100A6 transcription, thereby promoting the growth and metastasis of lung cancer cells.METHODS: The expression of HIF-1α or S100A6 in lung cancer cells was interfered with under normoxic and hypoxic conditions, and the cell proliferative, migratory, and invasive properties were assessed. The mechanism of HIF-1α-regulated TET2 and DNMT3 effects on S100A6 transcription under hypoxic conditions was further investigated.
RESULTS: Functionally, S100A6 overexpression promoted lung cancer cell proliferation and metastasis. S100A6 overexpression reversed the inhibitory effects of HIF-1α interference on the proliferation and metastasis of lung cancer cells. S100A6 was induced to express in a HIF-1α-dependent manner under hypoxic conditions, and silencing S100A6 or HIF-1α suppressed lung cancer cell proliferation and metastasis under hypoxic conditions. Further TCGA-LUAD database analysis revealed that S100A6 mRNA levels had a negative correlation with methylation levels. Mechanistically, CpG hypomethylation status in the S100A6 promoter HRE had an association with HIF-1α induction. TET2 was enriched in S100A6 promoter region of lung cancer cells under hypoxic conditions, whereas DNMT3a enrichment was reduced in S100A6 promoter region. HIF-1α-mediated S100A6 activation was linked to DNMT3a-associated epigenetic inactivation and TET2 activation.
INNOVATION: The activation of HIF-1α-mediated DNA methylation enzymes under hypoxic conditions regulated S100A6 transcription, thereby promoting lung cancer cell growth and metastasis.
CONCLUSION: In lung cancer progression, hypoxia-induced factor HIF-1α combined with DNA methylation modifications co-regulates S100A6 transcriptional activation and promotes lung cancer cell growth and metastasis.

DOI: https://doi.org/10.1089/ars.2023.0397