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17-Allylamino-17-Demethoxygeldanamycin Synergistically Potentiates Tumor Necrosis Factor–Induced Lung Cancer Cell Death by Blocking the Nuclear Factor-B Pathway

¹ Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico and ² West China Center of Medical Science, Sichuan University, Chengdu, China

Requests for reprints: Yong Lin, Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108. Phone: 505-348-9645 (Office) and 505-348-9140 (Lab); Fax: 505-348-4990; E-mail: ylin{at}lrri.org.

Nuclear factor-B (NF-B), a survival signal induced by tumor necrosis factor (TNF), contributes substantially to the resistance to TNF-induced cell death. Previous studies suggest that heat shock protein 90 (Hsp90) regulates the stability and function of receptor-interaction proteins (RIP) and IB kinase ß (IKKß), the key components of the TNF-induced NF-B activation pathway. In this study, we showed that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) was synergistic with TNF to induce apoptotic cell death in a panel of lung tumor-derived cell lines. Treatment with 17AAG caused degradation of RIP and IKKß that, in turn, blocked TNF-induced NF-B activation and antiapoptotic gene expression. The synergistic cytotoxicity was detected only when TNF treatment followed 17AAG preexposure. Importantly, the potentiation of cell death was abolished in NF-B-disabled cells that express a nondegradable IB mutant (IBAA). These results suggest that the cytotoxicity seen with 17AAG and TNF treatment results from blocking TNF-induced NF-B activation. The other components of the TNF receptor I signaling cascade were not altered, whereas TNF-induced c-Jun NH₂-terminal kinase activation and apoptosis were potentiated. A similar synergism for inducing apoptosis was also observed in 17AAG-treated and TNF-related apoptosis-inducing ligand (TRAIL)–treated cancer cells. Our results suggest that NF-B plays a key role in the resistance of lung cancer cells to TNF and TRAIL and that disabling this survival signal with 17AAG followed by TNF or TRAIL treatment could be an effective new therapeutic strategy for lung cancer. (Cancer Res 2006; 66(2): 1089-95)

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