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Inhibition of ANKRD1 sensitizes human ovarian cancer cells to endoplasmic reticulum stress-induced apoptosis.
- Source :
-
Oncogene [Oncogene] 2015 Jan 22; Vol. 34 (4), pp. 485-95. Date of Electronic Publication: 2014 Feb 17. - Publication Year :
- 2015
-
Abstract
- High expression of Ankyrin Repeat Domain 1 (ANKRD1) in ovarian carcinoma is associated with poor survival, and in ovarian cancer cell lines is associated with platinum resistance. Importantly, decreasing ANKRD1 expression using siRNA increases cisplatin sensitivity. In this study, we investigated possible mechanisms underlying the association of ANKRD1 with cisplatin response. We first demonstrated that cisplatin-induced apoptosis in ovarian cancer cell lines was associated with endoplasmic reticulum (ER) stress, evidenced by induction of Glucose-Regulated Protein 78 (GRP78), growth arrest- and DNA damage-inducible gene 153 (GADD153) and increased intracellular Ca(2+) release. The level of sensitivity to cisplatin-induced apoptosis was associated with ANKRD1 protein levels and poly (ADP-ribose) polymerase (PARP) cleavage. COLO 316 ovarian cancer cells, which express high ANKRD1 levels, were relatively resistant to cisplatin, and ER stress-induced apoptosis, whereas OAW42 and PEO14 cells, which express lower ANKRD1 levels, are more sensitive to ER stress-induced apoptosis. Furthermore, we show that overexpression of ANKRD1 attenuated cisplatin-induced cytotoxicity, and conversely siRNA knockdown of ANKRD1 sensitized ovarian cancer cells to cisplatin and ER stress-induced apoptosis associated with induction of GADD153, and downregulation of BCL2 and BCL-XL. Taken together, these results suggest that ANKRD1 has a significant role in the regulation of apoptosis in human ovarian cancer cells, and is a potential molecular target to enhance sensitivity of ovarian cancer to chemotherapy.
- Subjects :
- Cell Line, Tumor
Cisplatin therapeutic use
Drug Resistance, Neoplasm
Endoplasmic Reticulum Chaperone BiP
Female
Humans
Muscle Proteins analysis
Muscle Proteins antagonists & inhibitors
Nuclear Proteins analysis
Nuclear Proteins antagonists & inhibitors
Ovarian Neoplasms chemistry
Ovarian Neoplasms drug therapy
Poly(ADP-ribose) Polymerases metabolism
Proto-Oncogene Proteins c-bcl-2 analysis
Repressor Proteins analysis
Repressor Proteins antagonists & inhibitors
bcl-X Protein analysis
Apoptosis
Endoplasmic Reticulum Stress physiology
Muscle Proteins physiology
Nuclear Proteins physiology
Ovarian Neoplasms pathology
Repressor Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 34
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 24531715
- Full Text :
- https://doi.org/10.1038/onc.2013.566