Berberine Inhibits FOXM1 Dependent Transcriptional Regulation of POLE2 and Interferes With the Survival of Lung Adenocarcinoma

Abstract

Background: Berberine is one of the most interesting and promising natural anticancer drugs. POLE2 is involved in many cellular functions such as DNA replication and is highly expressed in a variety of cancers. However, the specific molecular mechanism of berberine interfering with POLE2 expression in lung adenocarcinoma (LUAD) is still unknown to a great extent.Method: The KEGG database (Release 91.0) and Gene Ontology (GO) category database were used for functional annotation of differentially expressed genes after berberine treatment. Reproducibility assessment using TCGA dataset. The biological functions of berberine in LUAD were investigated by a series of in vitro and in vivo experiments: MTT, colony formation, mouse xenograft and plasmid transfection. The molecular mechanisms of berberine were demonstrated by plasmid transfection, quantitative RT-PCR and Western blotting.Result: The elevated expression of FOXM1 and the high enrichment of DNA replication pathway were confirmed in LUAD by microarray and TCGA analysis, and were positively correlated with poor prognosis. Functionally, berberine inhibited the proliferation and survival of LUAD cell lines in vitro and in vivo. Mechanistically, berberine treatment down regulated the expression of FOXM1which closely related to survival, survival related genes in Cell cycle and DNA replication pathway, and significantly down regulated the expression of survival related POLE2. Interestingly, we found that the transcription factor FOXM1 could act as a bridge between berberine and POLE2.Conclusion: Berberine significantly inhibited LUAD progression via the FOXM1/POLE2, and FOXM1/POLE2 may act as a clinical prognostic factor and a therapeutic target for LUAD. Berberine may be used as a promising therapeutic candidate for LUAD patients.

Reverse predictive analysis of Rhizoma Pinelliae and Rhizoma Coptidis on differential miRNA target genes in lung adenocarcinoma

“…[46] Berberine can effectively inhibit the proliferation and migration of LUAD. [47] The study found that berberine blocked DNA replication in LUAD cells by down-regulating DNA polymerase epsilon 2 and DNA primase subunit 1 in LUAD cells. At the same time, Berberine has a down-regulating effect on the main gene expression biomarker (forkhead box M1) that can reflect the poor prognosis of pan-cancer, [47] which indicates that berberine has a good inhibitory effect on the development of LUAD cells throughout the cycle.…”

“…[47] The study found that berberine blocked DNA replication in LUAD cells by down-regulating DNA polymerase epsilon 2 and DNA primase subunit 1 in LUAD cells. At the same time, Berberine has a down-regulating effect on the main gene expression biomarker (forkhead box M1) that can reflect the poor prognosis of pan-cancer, [47] which indicates that berberine has a good inhibitory effect on the development of LUAD cells throughout the cycle. Palmatine is a class of isoquinoline alkaloids with highly effective biological activity and good water solubility and has shown a good effect in promoting apoptosis of adenocarcinoma cells in previous studies.…”

Multi-Target Potential of Berberine as an Antineoplastic and Antimetastatic Agent: A Special Focus on Lung Cancer Treatment

“…Further, the in vivo studies with Lewis lung carcinoma (LLC) cells in a transplanted tumor mouse model showed that in comparison to the control untreated group, Berberine treatment resulted in significantly higher tumor necrosis alongside a reduction in the expression levels of RRM1 , RRM2 , LIG1 , and POLE2 [ 102 ]. In continuation of the study, Ni et al analyzed the differential expression of genes in Berberine-treated A549 cells and in the lung adenocarcinoma cohort created by the Cancer Genome Atlas (TCGA) and suggested that Berberine interferes with tumor cell proliferation and progression primarily by downregulating the cell cycle and DNA replication related genes [ 92 ]. An overall suppression in the expression of mini-chromosome maintenance complex component 4 (MCM4 ), DNA polymerase alpha subunit 2 (POLA2 ), POLE2 , and DNA primase subunit 1 (PRIM1) in A549 cells treated with Berberine, which are involved in G1/S cell cycle transition and DNA replication, was observed.…”

“…An overall suppression in the expression of mini-chromosome maintenance complex component 4 (MCM4 ), DNA polymerase alpha subunit 2 (POLA2 ), POLE2 , and DNA primase subunit 1 (PRIM1) in A549 cells treated with Berberine, which are involved in G1/S cell cycle transition and DNA replication, was observed. Thus, as a mechanism, both in vitro and in vivo lung adenocarcinoma xenografts studies indicated Berberine-mediated downregulation of forkhead box protein M1 (FoxM1), an oncoprotein transcription factor, majorly inhibiting the POLE2 expression involved in DNA replication and affecting the overall survival of lung adenocarcinoma [ 92 ].…”

Network pharmacological analysis of corosolic acid inhibits hepatocellular carcinoma progression through P4HA2

“…Recently, network pharmacology and bioinformatics analysis have provided new ideas and solutions for the study of the mechanism for natural products (Wang et al 2021;Ni et al 2022). Bioinformatics analysis based on proteomics has been widely used to identify differential proteins after cancer chemotherapy (Niu et al 2020;Li et al 2021).…”