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Knockdown of MADD and c-FLIP overcomes resistance to TRAIL-induced apoptosis in ovarian cancer cells

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posted on 17.08.2012 by Liang-Cheng Li, Shankar Jayaram, Lakshmy Ganesh, Lixia Qian, Jacob JacobRotmensch, Ajay V. Maker, Bellur S. Prabhakar
Objective The clinical utility of tumor necrosis factor–related apoptosis–inducing ligand (TRAIL) in the treatment of established human malignancies is limited by the development of resistance to TRAIL. We hypothesized that knockdown of map-kinase activating death domain containing protein (MADD), a TRAIL-resistance factor, may overcome TRAIL resistance in ovarian cancer cells. Study Design MADD expression in resected ovarian cancer specimens and cell lines was quantified with the use of polymerase chain reaction. Sensitivity of ovarian cancer cell lines to TRAIL, with or without MADD knockdown, was assessed. Results MADD is expressed at relatively higher levels in human malignant ovarian cancer tissues and cell lines, compared with normal ovarian tissues. The cell lines OVCA429 and OVCAR3 were susceptible, and cell lines CAOV-3 and SKOV-3 were resistant to TRAIL. MADD knockdown in CAOV-3 cells, but not in SKOV-3 cells, conferred TRAIL sensitivity. Knockdown of cellular Fas-associated death domain–like interleukin-1 beta-converting enzyme–inhibitory protein (c-FLIP) in SKOV-3 cells increased spontaneous and TRAIL-induced apoptosis, which was further increased on MADD knockdown. Conclusion MADD/c-FLIPL knockdown can render TRAIL-resistant ovarian cancer cells susceptible to TRAIL.

History

Publisher Statement

NOTICE: this is the author’s version of a work that was accepted for publication in American Journal of Obstetrics and Gynecology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in American Journal of Obstetrics and Gynecology, [Vol 205, Issue 4, October 2011] DOI: 10.1016/j.ajog.2011.05.035. The original publication is available at www.elsevier.com.

Publisher

Elsevier

Language

en_US

issn

0002-9378

Issue date

01/10/2011

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