Asperolide A induces apoptosis and cell cycle arrest of human hepatoma cells with p53-Y220C mutant through p38 mediating phosphorylation of p53 (S33)

Asperolides A (AA), one of the new tetranorlabdane diterpenoids, is proved to inhibit the pro-liferation of lung cancer cells and bone metastasis of breast cancer cells. Herein, we report that AA induces apoptosis and cell cycle arrest of hepatoma cells. It intensely inhibits proliferation of Huh-7 cell, compared with HepG-2 and L02 cells. AA elevates the activity of mitogen-activated protein kinases (MAPKs), in which the activation of ERK and JNK improves cell survival. However, phosphorylation of p53 at S33 by p38 activation could be a principal factor in the AA-induced apoptosis and G2/M cell cycle arrest of Huh-7 cells. The S33 site of p53-Y220C mutant, as the specific activation site of p38, reactivates the wild-type function of mutant p53 protein, which leads to a higher sensitivity of Huh-7 cells to AA. These results provide new insights into the molecular mechanisms of AA as a developing mutant p53 rescue drug.

Automated summary

Asperolides A (AA), a new tetranorlabdane diterpenoid, has been shown to inhibit the proliferation of lung cancer cells and bone metastasis of breast cancer cells. In this study, researchers found that AA can induce apoptosis and cell cycle arrest in hepatoma cells. It specifically inhibits the proliferation of Huh-7 cells, compared to HepG-2 and L02 cells. The activation of ERK and JNK by AA contributes to cell survival, while the phosphorylation of p53 at S33 by p38 activation plays a crucial role in AA-induced apoptosis and G2/M cell cycle arrest in Huh-7 cells. The activation of the p53-Y220C mutant by p38 reactivates the wild-type function of the mutant p53 protein, leading to increased sensitivity of Huh-7 cells to AA. These findings provide valuable insights into the molecular mechanisms of AA as a potential mutant p53 rescue drug.