title: Inhibition of ANKRD1 sensitizes human ovarian cancer cells to endoplasmic reticulum stress-induced apoptosis.
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.
authors: 1] Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia [2] Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Y
authors: Y
authors: Lei
authors: Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: B R
authors: BR
authors: Henderson
authors: 1] Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia [2] Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: C
authors: C
authors: Emmanuel
authors: 1] Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead, New South Wales, Australia [2] Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia.
authors: P R
authors: PR
authors: Harnett
authors: 1] Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia [2] Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead, New South Wales, Australia [3] Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia.
authors: A
authors: A
authors: deFazio
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006801:Humans; D009124:Muscle Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009687:Nuclear Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012097:Repressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D051020:bcl-X Protein / Q000032:analysis
chemical_list: C491304:ANKRD1 protein, human; C494811:BCL2L1 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D009124:Muscle Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin