Bufalin targets the SRC-3/c-Myc pathway in chemoresistant cells to regulate metastasis induced by chemoresistance in colorectal cancer

Abstract Metastasis and chemoresistance are often major challenges in advanced-stage colorectal cancer. Recent studies have found extensive crosstalk between them. Previous studies have shown that bufalin has a therapeutic effect on both metastasis and drug resistance, but how bufalin affects chemoresistance-mediated metastasis remains unclear. In our study, we found that bufalin inhibited resistance-induced epithelial-mesenchymal transition (EMT) and angiogenesis, which in turn inhibited the resulting metastasis. In addition, we demonstrated that targeting of the SRC-3 protein by bufalin reduced the expression level of c-Myc and inhibited the prometastatic effect mediated by chemoresistance. Overexpression of SRC-3 or c-Myc reversed the inhibitory effect of bufalin on chemotherapeutic resistance, promoting metastasis. More interestingly, we also found that the clinical drug cinobufacini and its main active monomer bufalin reduced liver metastasis of colorectal cancer caused by chemoresistance in vivo. In conclusion, bufalin can target the SRC-3/c-Myc signaling pathway to affect the prometastatic effect of chemoresistant cells, suggesting that bufalin may be used as a new adjuvant antimetastatic therapy for colorectal cancer.