Scutellarein inhibits the development of colon cancer via CDC4-mediated RAGE ubiquitination

Scutellarein has been identified to serve an anti-tumor function in human colon cancer, but the underlying mechanisms remain largely unclear. The present study further investigated the effect and mechanism of scutellarein, extracted from wild chrysanthemum, in the progression of colon cancer. MTT, clone formation, flow cytometry and tumor-bearing mice assays were used to detect cell viability, clone formation, apoptosis and tumorigenesis, respectively. Western blot and quantitative PCR assays were performed for protein and mRNA expression detection. The results revealed that, compared with the control group, scutellarein treatment significantly inhibited the viability and induced the apoptosis of colon cancer cells (P<0.05), with significant decreases in receptor for advanced glycosylation end products (RAGE) protein expression and stability and an increase in RAGE ubiquitination (P<0.05). However, the effects of scutellarein exerted in cell apoptosis and viability were rescued by RAGE overexpression, and accelerated by RAGE knockdown. Additionally, it was observed that scutellarein treatment induced a significant increase in the expression of cell division control protein 4 (CDC4) compared with the control group (P<0.05), which was then verified to interact with RAGE protein and mediate its ubiquitination. Overexpression of CDC4 inhibited colon cancer cell viability and promoted the apoptosis of SW480 and T84 cells, whereas this function was weakened when RAGE was overexpressed. Furthermore, CDC4 downregulation significantly neutralized scutellarein functions in promoting cell apoptosis and inhibiting cell viability and tumorigenesis in colon cancer cells compared with the scutellarein group (P<0.05). In conclusion, the present study revealed that scutellarein inhibited the development of colon cancer through upregulating CDC4-mediated RAGE ubiquitination.