A gene expression signature-based approach reveals the mechanisms of action of the Chinese herbal medicine berberine

Abstract

Berberine (BBR), a traditional Chinese herbal medicine, was shown to display anticancer activity. In this study, we attempted to provide a global view of the molecular pathways associated with its anticancer effect through a gene expression-based chemical approach. BBR-induced differentially expressed genes obtained from the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) were analyzed using the Connectivity Map (CMAP) database to compare similarities of gene expression profiles between BBR and CMAP compounds. Candidate compounds were further analyzed using the Search Tool for Interactions of Chemicals (STITCH) database to explore chemical-protein interactions. Results showed that BBR may inhibit protein synthesis, histone deacetylase (HDAC), or AKT/mammalian target of rapamycin (mTOR) pathways. Further analyses demonstrated that BBR inhibited global protein synthesis and basal AKT activity, and induced endoplasmic reticulum (ER) stress and autophagy, which was associated with activation of AMP-activated protein kinase (AMPK). However, BBR did not alter mTOR or HDAC activities. Interestingly, BBR induced the acetylation of α-tubulin, a substrate of HDAC6. In addition, the combination of BBR and SAHA, a pan-HDAC inhibitor, synergistically inhibited cell proliferation and induced cell cycle arrest. Our results provide novel insights into the mechanisms of action of BBR in cancer therapy.

Berberine displays antitumor activity in esophageal cancer cellsin vitro

“…Our results showed that berberine treatment inhibited the phosphorylation of Akt and mTOR, as well as mTOR downstream target p70S6K, but enhanced the phosphorylation of AMPK. A previous study reported that, in breast cells, berberine transiently activated AMPK and inhibited AKT, but did not inhibit mTOR activity[22]. Our results showed that treatment with berberine induced sustained alterations (6-24 h) of increased levels of AKT and mTOR phosphorylation in KYSE-70 cells or increased level of AMPK phosphorylation in KYSE-70 cells.…”

Effect of new berberine derivatives on colon cancer cells

“…It has been used in Ayurvedic and Chinese medicines for hundreds of years and shows a wide range of pharmacological and biochemical effects [1][2][3]. This alkaloid has a definite potential to be used as drug in a wide spectrum of clinical applications because it is effective against hyperlipidemia, diabetes, metabolic syndrome, polycystic ovary syndrome, obesity, fatty liver disease, coronary artery disease, gastroenteritis, diarrhea, hypertension, neurodegeneration, and cancer [1][2][3]. Of note, the structure of BBR makes it an attractive natural lead compound for the introduction of various chemical modifications in appropriate positions of the skeleton [4].…”

Inhibitory effects of Berberine on the migratory and invasive abilities of cancer cells

“…Among the EMT-related genes were inhibited by berberine, high BMP7, NODAL and Snail1 gene expressions of metastatic prostate cancer tissues were associated with shorter survival of prostate cancer patients and provide potential therapeutic interventions. Our another recent study reveal novel anti-migratory function of berberine in breast cancer cells through increased acetylation of -tubulin to inhibit breast cancer cells migration [26] . In conclusion, berberine may represent a promising therapy for various cancers, potentially in the prevention the migration and invasion of cancer cells through inhibiting EMT-related genes.…”