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The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformins therapeutic efficacy in PCa.

A protocol for the synthesis of N, N′-alkyl aryl ureas and N, N′-dialkyl ureas by transition metal-catalyzed regioselective N3-alkylation of the N-monosubstituted ureas with alcohols was proposed and accomplished. In the presence of an iridium/base system, the desired N, N′-alkyl aryl ureas and N, N′-dialkyl ureas were obtained with 70-93 % yields, and no isomeric N1-alkylated and N3-dialkylated products were formed in all cases. From both synthetic and environmental point of views, the reaction is highly attractive because of easily available starting materials, high atom efficiency and the formation of water as the only side product. Apparently, the research opens up the design of regioselective N-alkylation of amines with alcohols based on the regioselective condensation of amines with aldehydes, facilitating the progress of the 'hydrogen autotransfer' (or 'hydrogen-borrowing') process. [ABSTRACT FROM AUTHOR]

The direct N-alkylation of 2-aminoimidazoles to give the corresponding 2-( N-alkylamino)imidazoles was accomplished using alcohols as alkylating agents in the presence of a [Cp*IrCl2]2/K2CO3 system. The iridium-catalyzed regioselective reaction is simple, efficient, general, and environmentally benign. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Methyltransferase 3 (METTL3) accelerates N6‐methyladenosine (m6A) modifications and affects cancer progression, including non‐small‐cell lung cancer (NSCLC). In this study, we aimed to explore the regulatory mechanisms of METTL3 underling NSCLC.Immunohistochemical assay, quantitative real‐time polymerase chain reaction (qRT‐PCR) assay, and western blot assay were conducted for gene expression. MTT assay and colony formation assay were performed to explore cell proliferation capacity. Cell apoptosis and THP‐1 cell polarization were estimated by flow cytometry analysis. Cell migration and invasion capacities were evaluated by transwell assay. Methylated RNA immunoprecipitation assay, dual‐luciferase reporter assay, actinomycin D treatment and RIP assay were performed to analyze the relationships of METTL3, insulin‐like growth factor 2 mRNA binding protein 1 (IGF2BP1), and transient receptor potential cation channel subfamily V member 1 (TRPV1). The functions of METTL3 and TRPV1 in vivo were investigated through establishing the murine xenograft model.TRPV1 expression was upregulated in NSCLC and related poor prognosis. TRPV1 silencing inhibited NSCLC cell growth and metastasis, induced NSCLC cell apoptosis, and repressed M2 macrophage polarization. The results showed that METTL3 and IGF2BP1 could regulate TRPV1 expression through m6A methylation modification. Moreover, METTL3 deficiency inhibited NSCLC cell growth, metastasis, and M2 macrophage polarization and facilitated NSCLC cell apoptosis, while TRPV1 overexpression restored the impacts. In addition, METTL3 knockdown restrained tumor growth in vivo via regulating TRPV1 expression.METTL3 bound to IGF2BP1 and enhanced IGF2BP1's m6A recognition of TRPV1 mRNA, thereby promoting NSCLC cell growth and metastasis, and inhibiting M2 macrophage polarization. [ABSTRACT FROM AUTHOR]

Identification of mucin modulators is of remarkable significance to facilitate mucin-based antineoplastic therapy. However, little is known about circular RNAs (circRNAs) on regulating mucins. Dysregulated mucins and circRNAs were identified via high-throughput sequencing and their relationships with lung cancer survival were analyzed in tumor samples of 141 patients. The biological functions of circRABL2B were determined via gain- and loss-of-function experiments and exosome-packaged circRABL2B treatment in cells, patient-derived lung cancer organoids and nude mice. We identified that circRABL2B was negatively correlated with MUC5AC. Patients with low circRABL2B and high MUC5AC displayed the poorest survival (HR=2.00; 95% CI=1.12-3.57). Overexpressed circRABL2B significantly inhibited cell malignant phenotypes, while it knock-down exerted opposite effects. CircRABL2B interacted with YBX1 to inhibit MUC5AC, and subsequently suppressed integrin β4/pSrc/p53 signaling and impoverished cell stemness, and promoted erlotinib sensitivity. Exosome-packaged circRABL2B exerted significant anti-cancer actions in cells, patient-derived lung cancer organoids and nude mice. Meanwhile, circRABL2B in plasma exosomes could distinguish early-stage lung cancer patients from healthy controls. Finally, we found circRABL2B was downregulated at the transcriptional level, and EIF4a3 involved the formation of circRABL2B. In conclusion, our data suggest that circRABL2B counteracts lung cancer progression via MUC5AC/integrin β4/pSrc/p53 axis, which provides a rationale to enhance the efficacy of anti-MUCs treatment in lung cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)