The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin

ObjectiveTo identify pathways that influence endometrial cancer (EC) cell sensitivity to cisplatin and to characterize the BCL2 antagonist of cell death (BAD) pathway as a therapeutic target to increase cisplatin sensitivity.MethodsEight EC cell lines (Ishikawa, MFE296, RL 95-2, AN3CA, KLE, MFE280, MFE319, HEC-1-A) were subjected to Affymetrix Human U133A GeneChip expression analysis of approximately 22,000 probe sets. In parallel, endometrial cell line sensitivity to cisplatin was quantified by MTS assay, and IC50 values were calculated. Pearson's correlation test was used to identify genes associated with response to cisplatin. Genes associated with cisplatin responsiveness were subjected to pathway analysis. The BAD pathway was identified and subjected to targeted modulation, and the effect on cisplatin sensitivity was evaluated.ResultsPearson's correlation analysis identified 1443 genes associated with cisplatin resistance (P < 0.05), which included representation of the BAD-apoptosis pathway. Small interfering RNA (siRNA) knockdown of BAD pathway protein phosphatase PP2C expression was associated with increased phosphorylated BAD (serine-155) levels and a parallel increase in cisplatin resistance in Ishikawa (P = 0.004) and HEC-1-A (P = 0.02) cell lines. In contrast, siRNA knockdown of protein kinase A expression increased cisplatin sensitivity in the Ishikawa (P = 0.02) cell line.ConclusionThe BAD pathway influences EC cell sensitivity to cisplatin, likely via modulation of the phosphorylation status of the BAD protein. The BAD pathway represents an appealing therapeutic target to increase EC cell sensitivity to cisplatin.

► Endometrial cancer cell cisplatin-sensitivity is associated with the expression of the BAD pathway, likely via phosphorylation of BAD protein. ► Modulation of BAD phosphorylation by inhibition of BAD kinases and phosphatases influences endometrial cancer cell sensitivity to cisplatin-induced apoptosis. ► The BAD pathway represents an appealing therapeutic target to increase endometrial cancer cell sensitivity to cisplatin.