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Bcl-2 overexpression reduces cisplatin cytotoxicity by decreasing ER-mitochondrial Ca2+ signaling in SKOV3 cells.
- Source :
-
Oncology reports [Oncol Rep] 2018 Mar; Vol. 39 (3), pp. 985-992. Date of Electronic Publication: 2017 Dec 19. - Publication Year :
- 2018
-
Abstract
- Recent studies have revealed that a small amount of cisplatin can penetrate into the nucleus and induce intranuclear DNA damage. Specifically, most cisplatin accumulates in and stresses different organelles, including mitochondria, endoplasmic reticulum (ER) and the cytosol, where apoptosis signaling is activated and magnified. Bcl-2, which is mainly localized to ER and mitochondria, is identified as a key regulator of survival and apoptosis. Bcl-2 is reported to block cisplatin-induced apoptosis via regulating Ca2+ signaling in a variety of cancer cell lines. However, its target molecule and the mechanism responsible for its inhibitory effect in ovarian cancer are undefined. The present study revealed that Bcl-2 overexpression reduced cisplatin-induced growth inhibition and apoptosis in SKOV3 human ovarian cancer cells. Furthermore, Bcl-2 inhibited cisplatin-induced Ca2+ release from the ER to the cytoplasm and mitochondria, which reduced cisplatin-induced ER stress-mediated apoptosis through the mitochondrial apoptotic pathway. The overexpression of Bcl-2 inhibited the cisplatin-induced increase in the number of ER-mitochondrial contact sites in SKOV3 human ovarian cancer cells. In addition, the present study provided evidence that Bcl-2 reduced the anticancer activity of cisplatin towards ovarian cancer cells in vivo. These results revealed that Bcl-2 attenuates cisplatin cytotoxicity via downregulating ER-mitochondrial Ca2+ signaling transduction. Thus, Bcl-2 which may be a potential therapeutic target for ovarian cancer.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Biomarkers, Tumor metabolism
Cell Proliferation drug effects
Endoplasmic Reticulum drug effects
Endoplasmic Reticulum metabolism
Endoplasmic Reticulum Stress drug effects
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Ovarian Neoplasms drug therapy
Ovarian Neoplasms metabolism
Signal Transduction
Tumor Cells, Cultured
Apoptosis drug effects
Calcium metabolism
Cisplatin pharmacology
Drug Resistance, Neoplasm
Endoplasmic Reticulum pathology
Membrane Potential, Mitochondrial drug effects
Ovarian Neoplasms pathology
Proto-Oncogene Proteins c-bcl-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2431
- Volume :
- 39
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Oncology reports
- Publication Type :
- Academic Journal
- Accession number :
- 29286126
- Full Text :
- https://doi.org/10.3892/or.2017.6164