TAT-fused IP3R-derived peptide enhances cisplatin sensitivity of ovarian cancer cells by increasing ER Ca2+ release

Abstract

Ovarian cancer is the most common gynecological malignancy. At present, cisplatin is used to treat ovarian cancer; however, the development of cisplatin resistance during therapy is a common obstacle to achieving favorable outcomes. Recently, the B-cell lymphoma 2 (Bcl-2) BH4 domain has been reported to mediate the prosurvival activity of Bcl-2 in cancer; however, the involvement of the BH4 domain of Bcl-2 in the cisplatin resistance of ovarian carcinoma cells is not entirely clear. In this study, we observed the cytoplasmic and mitochondrial levels of Ca2+ by confocal laser microscopy. We also detected cell apoptosis using western blot analysis and flow cytometry. The present study demonstrated that TAT-fused inositol 1,4,5-trisphosphate receptor-derived peptide (TAT-IDPS), which targets the BH4 domain of Bcl-2, increased cisplatin-induced Ca2+ flux from the endoplasmic reticulum (ER) into the cytosol and mitochondria. In addition, TAT-IDPS increased cisplatin-induced expression of mitochondrial apoptosis-associated proteins and ER stress-associated proteins. These results indicated that TAT-IDPS may enhance the cytotoxicity of cisplatin toward ovarian carcinoma cells by increasing ER Ca2+ release.