Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Tumor metastasis significantly impacts bladder cancer (BLCA) progression and patient outcomes.
• Previous research indicated mevalonate (MVA) pathway activation promotes BLCA cell migration, but the underlying mechanism remained unclear.

Purpose of the Study:

• To elucidate the mechanism by which the MVA pathway influences BLCA cell migration and metastasis.
• To identify key molecular players and potential therapeutic targets within this pathway for BLCA treatment.

Main Methods:

• Analysis of single-cell and bulk transcriptomic datasets to correlate MVA pathway enzyme expression with BLCA patient prognosis.
• Inhibition of the MVA pathway using farnesyl diphosphate synthase (FDPS) knockdown and pharmacological inhibitors (zoledronic acid, simvastatin).
• Investigating the role of geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) in BLCA cell migration, and identifying RhoB as a key effector.

Main Results:

• Elevated MVA pathway enzyme expression in BLCA correlates with poorer patient prognosis.
• Inhibition of the MVA pathway significantly reduced BLCA cell migration, an effect dependent on geranylgeranylation.
• RhoB, geranylgeranylated by the MVA pathway, influences BLCA metastasis via the ubiquitin-proteasome pathway and affects integrin β1 translocation.

Conclusions:

• The MVA pathway plays a critical role in bladder cancer metastasis.
• Geranylgeranylation of RhoB is a key mechanism by which the MVA pathway promotes BLCA cell motility.
• Targeting the MVA pathway, particularly geranylgeranylation, presents a promising therapeutic strategy for bladder cancer.