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Possible role of FLICE-like inhibitory protein (FLIP) in chemoresistant ovarian cancer cells in vitro

Oncogene volume 23, pages 6997–7004 (2004)Cite this article

Abstract

Chemoresistance is a major therapeutic problem and the current knowledge on cellular mechanisms involved is incomplete. In the present study, we have investigated the possible involvement of Fas-associated death domain-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein (FLIP) in ovarian cancer resistance by comparing chemosensitive (OV2008) and chemoresistant (C13*) ovarian cancer cells treated with cisplatin in vitro, and/or transfected with FLIP sense cDNA or FLIP small interfering RNA (siRNA) and determining FLIP protein content, cleavage of caspase-8 and caspase-3 and apoptosis. Cisplatin significantly decreased FLIP protein level, induced cleavage of caspase-8 and caspase-3 and apoptosis in a concentration-dependent manner in cisplatin-sensitive but not -resistant cells. While overexpression of FLIP-attenuated cisplatin-induced cleavage of caspase-8 and caspase-3 and apoptosis in chemosensitive cells, downregulation of FLIP in chemoresistant cells by siRNA increased apoptosis induced by cisplatin. These results suggest that FLIP plays a significant role in the regulation of apoptosis in human ovarian cancer cells and their sensitivity to cisplatin. This cell survival factor may be an important determinant in chemoresistance in ovarian cancer and may serve as a molecular target for the development of novel therapy for chemoresistant ovarian cancer.

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Abbreviations

DED:

death effector domain

DMSO:

dimethyl sulfoxide

FADD:

Fas-associated death domain

FasL:

Fas ligand

FBS:

fetal bovine serum

FLICE:

Fas-associated death domain-like interleukin-1β-converting enzyme

FLIP:

FLICE-like inhibitory protein

FLIPL:

long isoform of FLICE-like inhibitory protein

FLIPS:

short isoform of FLICE-like inhibitory protein

GFP:

green florescent protein

RPMI-1640:

Roswell Park Memorial Institute 1640

siRNA:

small interfering RNA

XIAP:

X-linked inhibitor of apoptosis protein

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Acknowledgements

This work was supported by grants from the Canadian Institute of Health Research (MOP-15691) and the National Cancer Institute of Canada (with funds from the Canadian Cancer Society, Grant # 013335) to BKT. MRA is a recipient of a scholarship from the Ministry of Health and Medical Education, Government of Iran.

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Authors and Affiliations

  1. Reproductive Biology Unit and Division of Gynecologic Oncology, Departments of Obstetrics and Gynaecology, University of Ottawa, Ottawa, Ontario, Canada

    Mohammad R Abedini, Qing Qiu, Xiaojuan Yan & Benjamin K Tsang

  2. Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

    Mohammad R Abedini, Qing Qiu, Xiaojuan Yan & Benjamin K Tsang

  3. Ottawa Health Research Institute, Ottawa, K1Y 4E9, Ontario, Canada

    Mohammad R Abedini, Qing Qiu, Xiaojuan Yan & Benjamin K Tsang

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  1. Mohammad R Abedini
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  2. Qing Qiu
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Correspondence to Benjamin K Tsang.

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Abedini, M., Qiu, Q., Yan, X. et al. Possible role of FLICE-like inhibitory protein (FLIP) in chemoresistant ovarian cancer cells in vitro. Oncogene 23, 6997–7004 (2004). https://doi.org/10.1038/sj.onc.1207925

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