Villosol reverses 5-FU resistance in colorectal cancer by inhibiting the CDKN2A gene regulated TP53-PI3K/Akt signaling axis

• Published in: Journal of ethnopharmacology 2024-05, Vol.325, p.117907-117907, Article 117907
• Main Authors: Chen, Han, Deng, Jiao, Hou, Tie-Wei, Shan, Yong-Qi
• Format: Article
• Language: English
• Subjects: 5-FU resistance; Animals; Apoptosis; CDKN2A; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - pharmacology; Drug Resistance, Neoplasm; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Genes, p16; Humans; Lactones; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; TP53-PI3K/Akt axis; Tumor Suppressor Protein p53 - genetics; Villosol; Xenograft Model Antitumor Assays
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2024.117907

Patrinia villosa (Juss.) (PV) is the drug of choice in traditional Chinese medicine for the treatment of colorectal cancer (CRC) and has achieved reliable efficacy in clinic. Villosol is the active ingredient in PV. However, the molecular mechanism by which Villosol reverses chemoresistance in CRC remains unclear. Analysis of the molecular mechanism by which Villosol, the active ingredient of PV, reverses CRC/5-FU resistance through modulation of the CDKN2A gene was validated by network pharmacology techniques and experiments. We identified CDKN2A as a gene associated with 5-FU resistance through gene chip analysis. Next, we conducted a series of functional analyses in cell lines, animal samples, and xenograft models to investigate the role, clinical significance, and abnormal regulatory mechanisms of CDKN2A in 5-FU resistance in CRC. In addition, we screened and obtained a raw ingredient called Villosol, which targets CDKN2A, and investigated its pharmacological effects. Analysis of CRC cells and animal samples showed that the upregulation of CDKN2A expression was strongly associated with 5-FU resistance. CRC cells overexpressing CDKN2A showed reduced sensitivity to 5-FU and enhanced tumor biology in vitro. Inhibition of aberrant activation of CDKN2A enhances the expression of TP53. Mechanistically, overexpression of CDKN2A activates the PI3K/Akt pathway and induces resistance to 5-FU. Villosol inhibited CDKN2A, and CRC/5-FU cells regained sensitivity to 5-FU. Villosol effectively reverses 5-FU resistance through the CDKN2A-TP53-PI3K/Akt axis. Changes in CDKN2A gene expression can be used to predict the response of CRC patients to 5-FU therapy. Additionally, inhibiting CDKN2A activation with Villosol may present a new approach to overcoming 5-FU resistance in clinical settings. [Display omitted] •Villosol reversal of CRC/5-FU resistance studied.•The efficacy of 5-FU is altered when the CDKN2A gene is interfered with by Villosol.•CDKN2A mediates 5-FU resistance through the P53-PI3K/Akt pathway.•Villosol downregulates CDKN2A gene expression and reduces 5-FU resistance in vitro and in vivo.