MG132-mediated Suppression of the Ubiquitin-proteasome Pathway Enhances the Sensitivity of Endometrial Cancer Cells to Cisplatin.

Background: Tumor cell resistance to cisplatin is a common challenge in endometrial cancer chemotherapy, stemming from various mechanisms. Targeted therapies using proteasome inhibitors, such as MG132, have been investigated to enhance cisplatin sensitivity, potentially offering a novel treatment approach.

Objective: The aim of this study was to investigate the effects of MG132 on cisplatin sensitivity in the human endometrial cancer (EC) cell line RL95-2, focusing on cell proliferation, apoptosis, and cell signaling.

Methods: Human endometrial cancer RL95-2 cells were exposed to MG132, and cell viability was assessed in a dose-dependent manner. The study evaluated the effect of MG132 on cisplatin-induced proliferation inhibition and apoptosis, correlating with caspase-3 activation and reactive oxygen species (ROS) upregulation. Additionally, we examined the inhibition of the ubiquitin-proteasome system and the expression of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and IL-13 during MG132 and cisplatin co-administration.

Results: MG132 exposure significantly reduced cell viability in a dose-dependent manner. It augmented cisplatin- induced proliferation inhibition and enhanced apoptosis, correlating with caspase-3 activation and ROS upregulation. Molecular analysis revealed a profound inhibition of the ubiquitin-proteasome system. MG132 also significantly increased the expression of cisplatin-induced pro-inflammatory cytokines, suggesting a transition from chronic to acute inflammation.

Conclusion: MG132 enhances the therapeutic efficacy of cisplatin in human EC cells by suppressing the ubiquitin- proteasome pathway, reducing cell viability, enhancing apoptosis, and shifting the inflammatory response. These findings highlighted the potential of MG132 as an adjuvant in endometrial cancer chemotherapy. Further research is needed to explore detailed mechanisms and clinical applications of this combination therapy.