LAPTM4B counteracts ferroptosis via suppressing the ubiquitin-proteasome degradation of SLC7A11 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.

Quantitative analysis of the profiles of twelve major compounds in Gentiana straminea Maxim. Roots by LC-MS/MS in an extensive germplasm survey in the Qinghai-Tibetan plateau.

ETHNOBOTANICAL RELEVANCE: Gentiana straminea Maxim. is a well-known Tibetan traditional herb, which has been used to treat rheumatic arthritis, iceteric hepatitis, and other diseases for thousands years. However, there is still lack of comprehensive active constituents profiling of this species throughout the Qinghai-Tibet Plateau (QTP). AIM OF STUDY: This study was designed to provide a comprehensive quality map of G.straminea germplasm based on twelve active constituents (loganic acid, gentiopicroside, swertiamarin, sweroside, 6-O-ß-D-glucosylgentiopicroside, oleanic acid, morroniside, trilobatin, isoorientin, isovite, Shanzhisidemethylester and quercetin) on the QTP. MATERIALS AND METHODS: G.straminea root samples collected throughout QTP in the flowering period were analyzed by the LC-MS/MS. Statistics analysis methods PCA, clustering and ecological regions analysis for G.straminea constituents differentiation was demonstrated. RESULTS: The active constituents varied greatly across the QTP; the majority of constituents were secoiridoid derivatives, with gentiopicroside being the most abundant compound. Most constituents were significantly affected by the latitudes and altitudes other than longitudes. PCA and hierarchical clustering analysis showed that all samples could be separated into six distinct groups, and 15 populations showed the highest constituent abundances. Further, geographical region analysis showed that the highest quality populations mainly located near the source region of Yellow River, especially in the Qinghai and Sichuan areas. Additionally, correlation analysis showed that there were relationships among genetiopicroside, loganic acid, and other compounds, which might be related to the enzymatic pathways involved in the metabolism of these constituents. CONCLUSION: LC-MS/MS method allowed separation of quality profiling of G.straminea on the QTP, 15 populations showed the highest constituent abundances. In six geographical groups, the highest quality populations mainly located near the source region of Yellow River, especially in the Qinghai and Sichuan areas, which may be due to the climate caused by the westerlies and Indian Ocean monsoons in the QTP.

Long non­coding RNA MEG3 inhibits cell migration and invasion of non­small cell lung cancer cells by regulating the miR­21­5p/PTEN axis.

Long non­coding RNAs (lncRNAs) are involved in the occurrence and progression of numerous types of cancer. The aim of the present study was to evaluate the effect of the lncRNA maternally expressed gene 3 (MEG3) on the migration and invasion of non­small cell lung cancer (NSCLC) H1299 and PC9 cells. Reverse transcription­quantitative (RT­q)PCR analysis showed that MEG3 was downregulated in NSCLC PC9 and H1299 cells. Additionally, bioinformatics analysis indicated that MEG3 sponges microRNA (miR)­21­5p; miR­21­5p was predicted to target the phosphatase and tensin homolog (PTEN) 3'­untranslated region sequence. MEG3 overexpression led to miR­21­5p suppression and PTEN upregulation in PC9 and H1299 cells, as detected by RT­qPCR. Subsequently, western blot analysis confirmed that MEG3 overexpression enhanced PTEN expression levels and inhibited the PI3K/AKT signaling pathway in NSCLC cells. These effects were attenuated by miR­21­5p. Dual luciferase assay supported the sponging effect of MEG3 on miR­21­5p and validated the direct interaction between miR­21­5p and PTEN. Furthermore, Transwell assay demonstrated that MEG3 overexpression had an inhibitory effect on cell migration and invasion. MEG3 overexpression also mediated epithelial­to­mesenchymal transition by significantly enhancing E­cadherin and decreasing N­cadherin, Vimentin and matrix metalloprotein 9 expression levels in NSCLC cells, as indicated by western blot analysis. These changes were partially reversed by an miR­21­5p mimic. These results indicated that MEG3 acted as a tumor suppressor that inhibited NSCLC cell migration and invasion via sponging miR­21­5p, which, in turn, enhanced the expression levels of PTEN, in part via the PI3K/AKT signaling pathway. The results of the present study have suggested the potential of MEG3 as a novel therapeutic target for NSCLC treatment.

Terpenes isolated from Polyalthia simiarum and their cytotoxic activities.

Two new C31 triterpenes, polysimiaric acid A (1) and B (2) as well as one new clerodane diterpenoid, 16,16-dimethoxy-cleroda-3,13Z-dien-15-oic acid (3), together with six known compounds were isolated from Polyalthia simiarum. Their structures were determined by analysis of 1D and 2D NMR data. Three new compounds were tested for their cytotoxicity against five human tumour cell lines. Compound 3 showed cytotoxic activities against SMMC-7721 with the IC50 value of 22.43 µM.

m6A RNA methylation regulators could contribute to the occurrence of chronic obstructive pulmonary disease.

N6-methyladenosine (m6A) RNA methylation, the most prevalent internal chemical modification of mRNA, has been reported to participate in the progression of various tumours via the dynamic regulation of m6A RNA methylation regulators. However, the role of m6A RNA methylation regulators in chronic obstructive pulmonary disease (COPD) has never been reported. This study aimed to determine the expression and potential functions of m6A RNA methylation regulators in COPD. Four gene expression data sets were acquired from Gene Expression Omnibus. Gene ontology function, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, weighted correlation network analysis and protein-protein interaction network analysis were performed. The correlation analyses of m6A RNA methylation regulators and key COPD genes were also performed. We found that the mRNA expressions of IGF2BP3, FTO, METTL3 and YTHDC2, which have the significant associations with some key genes enriched in the signalling pathway and biological processes that promote the development progression of COPD, are highly correlated with the occurrence of COPD. In conclusion, six central m6A RNA methylation regulators could contribute to the occurrence of COPD. This study provides important evidence for further examination of the role of m6A RNA methylation in COPD.