The role of IGF2BP3/SPOP/c-Myc loop in paclitaxel resistance of endometrial cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Paclitaxel is a primary chemotherapy for endometrial cancer (EC).
• Drug resistance limits paclitaxel's clinical efficacy in EC.
• Identifying resistance mechanisms is crucial for improving treatment outcomes.

Purpose of the Study:

• To investigate the role of IGF2BP3 in paclitaxel resistance in EC.
• To elucidate the molecular mechanism linking IGF2BP3, c-Myc, and paclitaxel resistance.
• To explore therapeutic strategies targeting this pathway.

Main Methods:

• Cell culture and in vivo models of paclitaxel-resistant EC.
• Western blotting and quantitative PCR to assess protein and mRNA levels.
• CRISPR/Cas9 gene editing to reduce IGF2BP3 expression.
• Treatment with paclitaxel and c-Myc inhibitor (10058-F4).

Main Results:

• IGF2BP3 is significantly elevated in paclitaxel-resistant EC cells.
• Reducing IGF2BP3 enhances EC cell sensitivity to paclitaxel in vitro and in vivo.
• IGF2BP3 stabilizes c-Myc by inhibiting SPOP-mediated degradation, forming a positive feedback loop.
• Combined treatment with paclitaxel and a c-Myc inhibitor restores sensitivity in resistant cells.

Conclusions:

• IGF2BP3-mediated c-Myc accumulation is a key mechanism of paclitaxel resistance in EC.
• Targeting the IGF2BP3/c-Myc axis offers a promising therapeutic strategy for overcoming paclitaxel resistance in EC.
• This study provides novel insights for developing effective treatments for resistant endometrial cancer.