PD173074 blocks G1/S transition via CUL3-mediated ubiquitin protease in HepG2 and Hep3B cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Fibroblast growth factor receptors (FGFRs) are implicated in various human cancers.
• FGFRs, particularly FGFR4, are overexpressed in hepatocellular carcinoma (HCC).
• The precise mechanisms of FGFR4's role in HCC progression are not fully understood.

Purpose of the Study:

• To investigate the role of FGFR4 in hepatocellular carcinoma (HCC) cell lines.
• To elucidate the underlying molecular mechanisms of FGFR4-mediated proliferation in HCC.
• To evaluate the therapeutic potential of inhibiting FGFR4 in HCC.

Main Methods:

• Utilized PD173074, a specific FGFR4 inhibitor, on HCC cell lines (HepG2 and Hep3B).
• Assessed cell cycle progression using cell arrest analysis.
• Analyzed protein expression levels via Western blot and gene expression via RT-qPCR.

Main Results:

• PD173074 treatment induced G1 phase arrest and inhibited proliferation in HepG2 and Hep3B cells.
• Inhibition of FGFR4 decreased key proteins including P-FRS2α, P-ERK, CDK2, cyclin E, and nuclear NF-κB (p65).
• PD173074 increased ubiquitin and CUL3 levels, promoting cyclin E degradation, and decreased miR-141 expression.

Conclusions:

• FGFR4 plays a significant role in HCC proliferation through the ERK/CUL3/cyclin E signaling pathway.
• Targeting FGFR4 with inhibitors like PD173074 demonstrates therapeutic promise for HCC.
• This study provides a potential theoretical foundation for developing FGFR4-targeted therapies for HCC.