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Inhibition of ANKRD1 sensitizes human ovarian cancer cells to endoplasmic reticulum stress-induced apoptosis

Oncogene volume 34, pages 485–495 (2015)Cite this article

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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 Ca2+ 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.

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Acknowledgements

This work was supported by grants from Cancer Council New South Wales, Australia and Cancer Australia (Project 632595). Special thanks to Dr Maggie Wang, Westmead Millennium Institute Flow Cytometry Facility, for her help with analysis.

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Authors and Affiliations

  1. Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia

    Y Lei, C Emmanuel & A deFazio

  2. Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead, New South Wales, Australia

    Y Lei, B R Henderson, C Emmanuel, P R Harnett & A deFazio

  3. Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia

    P R Harnett & A deFazio

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Paul Harnett and Anna deFazio jointly hold a patent related to ANKRD1 but have received no financial benefit. The remaining authors declare no conflict of interest.

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Lei, Y., Henderson, B., Emmanuel, C. et al. Inhibition of ANKRD1 sensitizes human ovarian cancer cells to endoplasmic reticulum stress-induced apoptosis. Oncogene 34, 485–495 (2015). https://doi.org/10.1038/onc.2013.566

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