Alantolactone curbs the malignant progression of bladder cancer partly via the HSP90AB1/LRP5/β-catenin axis

Bladder Cancer (BCa) represents a global health problem. Traditional Chinese medicine has a long history of treating cancers. This study has been conducted to illustrate the anti-cancer effects of alantolactone (ALT) in BCa and to explore the potential mechanism. The effects of ALT on the malignant behavior of T24 and TCCSUP cells were investigated. Bioinformatic methods were utilized to predict potential targets of ALT. Cells were infected with lentiviral overexpression vectors for heat shock protein HSP 90-beta (HSP90AB1) or treated with the β-catenin signaling inhibitor MSAB to explore their effects on BCa cell behaviors. The effects on tumorigenesis were also analyzed in a xenograft tumor model. ALT markedly reduced the proliferation, migration, and invasion of BCa cells and induced Apoptosis. ALT treatment was associated with decreased HSP90AB1 levels in BCa cells and increased low-density lipoprotein receptor-related protein 5 (LRP5) ubiquitination, thereby impairing β-catenin activation. HSP90AB1 overexpression attenuated the anti-cancer effects of ALT, while MSAB repressed the malignant progression of BCa cells promoted by HSP90AB1 overexpression. Forced overexpression of HSP90AB1 enhanced BCa development in vivo, which was mitigated by MSAB. In conclusion, our findings suggest that ALT exerts anti-cancer activity in BCa, potentially through modulation of HSP90AB1 and β-catenin signaling pathways.

Alantolactone; Bladder cancer; HSP90AB1; LRP5/β-catenin; Ubiquitination.