Glucose and Cell Context-Dependent Impact of BMI-1 Inhibitor PTC-209 on AKT Pathway in Endometrial Cancer Cells

Purpose: In our study, the glucose and cell context-dependent impact of the BMI-1 inhibitor PTC-209 on the Akt pathway in endometrial Cancer cells was determined.

Methods: The expression of BMI-1 was inhibited by PTC-209 in endometrial Cancer cells HEC-1A and Ishikawa stimulated with Insulin and grown in different glucose concentrations. The migration, invasion, viability, and proliferative potential after PTC-209 treatment was assessed using wound-healing, Transwell assay, Matrigel-coated inserts, and MTT tests. Chromatin immunoprecipitation was used to determine the localization of BMI-1 protein at promoter sites of the genes tested.

Results: BMI-1 inhibition caused an increase in PHLPP1/2 expression and a decrease in phospho-AKT level in both cell lines. The glucose concentration and Insulin stimulation differentially impact the Akt pathway through BMI-1 in cells differing in PTEN statuses. The expression of BMI-1 is dependent on the glucose concentration and Insulin stimulation mostly in PTEN positive HEC-1A cells. In high glucose concentrations, BMI-1 affects Akt activity through PHLPPs and in hypoglycemia mostly through PTEN. BMI-1 inhibition impacts on genes involved in SNAIL, SLUG, and CDH1 and reduces endometrial Cancer cells' migratory and invasive potential.

Conclusions: Our results indicate that the relationship between BMI-1 and phosphatases involved in Akt regulation depends on the glucose concentration and Insulin stimulation.

AKT pathway; BMI-1; EMT; endometrial cancer cells; glucose; insulin.