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

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• 作者：Liang-Cheng Li ; PhD^a ; Shankar Jayaram ; PhD^a ; Lakshmy Ganesh ; MS^a ; Lixia Qian ; BS^a ; Jacob Rotmensch ; MD^c ; Ajay V. Maker ; MD^a ; ^b ; Bellur S. Prabhakar ; PhD^a ; ^{bprabhak@uic.edu}
• 关键词：apoptosis ; c-FLIP ; IG20 ; MADD ; ovarian cancer ; shRNA
• 刊名：American Journal of Obstetrics and Gynecology
• 出版年：2011
• 出版时间：October, 2011
• 年：2011
• 卷：205
• 期：4
• 页码：362.e12-362.e25
• 全文大小：3016 K

文摘

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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-FLIP_L knockdown can render TRAIL-resistant ovarian cancer cells susceptible to TRAIL.