The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial–Mesenchymal Transition

Abstract

Berberine hydrochloride (BBR) could inhibit the proliferation, migration, and invasion of various cancer cells. As the only enzyme for the de novo synthesis of ribonucleotides, RRM2 is closely related to the development of tumorigenesis. However, not much is currently known about the functional roles of RRM2 in breast cancer (BRCA), and whether BBR regulates the migration and invasion of BRCA cells by regulating the expression of RRM2 remains to be determined. We study the effects of BBR on BRCA cell proliferation in vitro and tumorigenesis in vivo by using colony formation assays, EdU assays, and xenograft models. Transcriptome sequencing, the random forest algorithm, and KEGG analysis were utilized to explore the therapeutic target genes and relative pathways. The expression of RRM2 in BRCA patients was analyzed with The Cancer Genome Atlas (TCGA) dataset, the GEPIA website tool, the Gene Expression Omnibus (GEO) database, and the UALCAN database. The survival probability of BRCA patients could be predicted by survival curve and nomogram analysis. Molecular docking was used to explore the affinity between BBR and potential targets. Gain- and loss-of-function methods were employed to explore the biological process in RRM2 participants. We comprehensively investigated the pharmacological characteristics of BBR on BRCA cell lines and discovered that BBR could inhibit the proliferation of BRCA cells in vitro and in vivo. Combining transcriptome sequencing and KEGG analysis, we found that BBR mainly affected the biological behavior of BRCA cells via HIF-1α and AMPK signal pathways. Additionally, by using bioinformatics and molecular docking, we demonstrated that RRM2 plays an oncogenic role in BRCA samples and that it acts as the hub gene of BBR on BRCA cells. Knockdown and overexpression studies indicated that RRM2 promoted BRCA cell migration as well as invasion in vitro by affecting the epithelial-to-mesenchymal transition (EMT). Our study demonstrated the significance of BBR regulating HIF-1α and AMPK signaling pathways in BRCA cells. Moreover, we revealed the carcinogenic role and potential mechanism of RRM2 as a core regulatory factor of BBR in BRCA in controlling BRCA invasion, migration, and EMT, suggesting that RRM2 may be a therapeutic target and prognostic biomarker for BRCA therapy.

Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers

“…Multiple studies have reported a direct link between the overexpression of RRM2 in breast cancers and increased cell proliferation and invasiveness, as well as drug and chemotherapy resistance [ 12 , 13 , 29 , 31 ]. Previously, we found that RRM2 is upregulated in ER− and drug-resistant breast cancer cells, rationalizing our hypothesis of targeting ribonucleotide reductase for ER+ as well as ER− breast cancer treatment [ 12 , 13 , 14 ].…”

Higher concentration of P7C3 than required for neuroprotection suppresses renal cell carcinoma growth and metastasis

“…In melanoma, RRM2 could enhance melanoma grow and promote cellular senescence 51 . In breast cancer, RRM2 accelerated cell migration and invasion via regulating epithelial-mesenchymal transition (EMT) process 52 . In head and neck and lung cancers, knockdown of RRM2 caused cell apoptosis via accelerating the degradation of Bcl-2 25 .…”

Carrier-Free Self-Assembled Nanomedicines for Promoting Apoptosis and Inhibiting Proliferation in Hepatocellular Carcinoma

“…Berberine (BBR) is a natural isoquinoline alkaloid isolated from plants of the genus Berberis, with therapeutic effects on gastroenteritis, hyperlipidemia, coronary heart disease, and other diseases. − Notably, BBR showed inhibition of tumor cell proliferation, migration, and invasion in a variety of tumors. , Studies have shown that BBR not only has the ability to selectively reduce the viability of HCC cells without affecting normal hepatocytes but also effectively induces cell cycle arrest in the G1/S phase . AMP-activated protein kinase (AMPK), a metabolism-sensitive protein kinase, is involved in the regulation of cell growth, metabolism, apoptosis, autophagy, proliferation, and other physiological processes. − AMPK has a strong pro-apoptotic potential under activated conditions, and BBR induces selective apoptosis in HCC cells by inhibiting the expression of the antiapoptotic factor BCL-2 and through an AMPK-mediated mitochondrial/caspase pathway. , Similarly, AKT is a serine/threonine kinase that plays a major role in the PI3K/AKT signaling pathway and is involved in regulating the cell cycle, autophagy, and apoptotic processes. , Clinical findings have shown that higher levels of phosphorylated (p)-AKT in tumors are one of the major contributors to the increase in tumor drug resistance. , BBR can also inhibit tumor progression and overcome tumor drug resistance through PI3K/AKT. , BBR is a potential natural anticancer drug due to its multiple anticancer targets and low biological toxicity.…”