MAPK/AP-1 pathway regulates benzidine-induced cell proliferation through the control of cell cycle in human normal...

Area of Science:

• Urothelial Carcinogenesis
• Molecular Biology
• Cancer Research

Background:

• Bladder cancer is a common urinary tract malignancy, with long-term benzidine exposure as a significant risk factor.
• The precise mechanisms underlying benzidine-induced bladder cancer, particularly its effects on cell proliferation and the involvement of MAPKs, remain incompletely understood.
• Dysregulated cell proliferation is a hallmark of cancer initiation and progression.

Purpose of the Study:

• To investigate the impact of benzidine on cell proliferation in human uroepithelial cells (SV-HUC-1).
• To elucidate the role of mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) signaling in benzidine-induced cellular changes.
• To explore potential therapeutic targets for benzidine-initiated bladder tumorigenesis.

Main Methods:

• Utilized SV-40 immortalized human uroepithelial cells (SV-HUC-1) for in vitro studies.
• Assessed benzidine's effects on cell proliferation, cell cycle progression (G1 to S phase transition), and cell cycle-associated gene expression.
• Investigated the activation status of MAPKs (ERK1/2, p38, JNK) and AP-1 signaling pathways following benzidine exposure.
• Evaluated the efficacy of MAPK-specific inhibitors in reversing benzidine-induced proliferation.

Main Results:

• Benzidine exposure significantly enhanced SV-HUC-1 cell proliferation.
• Benzidine promoted cell cycle transition from G1 to S phase and altered the expression of related genes at mRNA and protein levels.
• Benzidine activated key MAPKs (ERK1/2, p38, JNK) and their downstream target, AP-1.
• Inhibition of MAPK pathways effectively reversed benzidine-induced cell proliferation.

Conclusions:

• Benzidine promotes bladder cell proliferation through the activation of the MAPK/AP-1 signaling pathway.
• This pathway activation is a critical mechanism in benzidine-induced bladder cancer initiation.
• Findings offer novel insights into benzidine carcinogenesis and potential avenues for cancer prevention strategies.