RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in             MCF-7 cells and suppresses the transcriptional activity of NF-κB.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is             a member of the TNF family of cytokines, which can induce apoptotic cell death             in a variety of tumor cells or transformed cells, yet, it is relatively non-toxic             to most normal cells. Consequently, TRAIL was thought to be a promising agent             for cancer therapy. However, recent research reports revealed that many tumors             are unresponsive to TRAIL treatment. Apoptotic agents were identified that when             used in combination with TRAIL can sensitize tumor cells to TRAIL-mediated apoptosis.             It was demonstrated that MEKK3-siRNA sensitized MCF-7 cells to TRAIL cytoxicity.             In addition, we investigated the discrepancy of the expression of MEKK3 in breast             cancers. It was concluded that elevated MEKK3 expression is found at high frequencies             in breast cancer compared to normal breast tissue. Further experiments on the             signal machinery showed that MEKK3-siRNA increased the sensitivity of MCF-7 cells             to TRAIL by suppressing the transcription activity of NF-κB, and enhancing the             caspase-processing to generate executive apoptotic signals. These findings indicate             that down-regulation of MEKK3 by siRNA approaches will lead to successful treatment             of human breast cancer with TRAIL.
Department of General Surgery, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, PR China. guoshyu@sina.com
Shan-Yu
SY
Guo
Shou-Gui
SG
Liu
Lei
L
Liu
Xiao-Jian
XJ
Zhou
Yan
Y
Gu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D048748:MAP Kinase Kinase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; D011065:Poly(ADP-ribose) Polymerases; D048748:MAP Kinase Kinase Kinase 3