NDLI: Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by siRNA silencing of tumor necrosis factor receptor-associated factor 2

Content Provider	PubMed Central
Author	Zheng, Min Morgan-lappe, Susan E. Yang, Jie Bockbrader, Katrina M. Pamarthy, Deepika Thomas, Dafydd Fesik, Stephen W. Sun, Yi
Abstract	Radiotherapy combined with chemotherapy is the treatment of choice for glioblastoma and locally advanced lung cancer, but radioresistance of these two types of cancer remains a significant therapeutic hindrance. To identify molecular target(s) for radiosensitization, we screened a siRNA library targeting all protein kinases and E3 ubiquitin ligases in the human genome and identified TRAF2 (TNF Receptor-associated factor 2). Silencing of TRAF2 using siRNA caused a significant growth suppression of glioblastoma U251 cells and moderately sensitized these radioresistant cells to radiation. Overexpression of a RING deleted dominant negative TRAF2 mutant, also conferred radiosensitivity; whereas over-expression of wild type TRAF2 significantly protected cells from radiation-induced killing. Likewise, siRNA silencing of TRAF2 in radioresistant lung cancer H1299 cells caused growth suppression and radiosensitization, whereas overexpression of wild type TRAF2 enhanced radioresistance in a RING ligase-dependent manner. Moreover, siRNA silencing of TRAF2 in UM-SCC-1 head and neck cancer cells also conferred radiosensitization. Further support for the role of TRAF2 in cancer comes from the observations that TRAF2 is overexpressed in both lung adenocarcinoma tissues and multiple lung cancer cell lines. Importantly, TRAF2 expression was very low in normal bronchial epithelial NL20 cells, and TRAF2 silencing had a minimal effect on NL20 growth and radiation sensitivity. Mechanistically, TRAF2 silencing blocks the activation of the NF-kB signaling pathway, and down-regulates a number of G2/M cell cycle control proteins, resulting in enhanced G2/M arrest, growth suppression, and radiosensitization. Our studies suggest that TRAF2 is an attractive drug target for anti-cancer therapy and for radiosensitization.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-08-0632
Ending Page	7578
Page Count	9
Starting Page	7570
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	18
Volume Number	68
Language	English
Publisher Date	2008-09-15
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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