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Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Is Required for Tumor Necrosis Factor –Mediated Sensitization of Human Breast Cancer Cells to Chemotherapy

Program in Molecular Biology and Human Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan

Requests for reprints: Gen Sheng Wu, Program in Molecular Biology and Human Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201. Phone: 313-833-0715, ext. 2328; Fax: 313-831-7518; E-mail: wug{at}karmanos.org.

Tumor necrosis factor (TNF) induces apoptosis and sensitizes cancer cells to chemotherapy, but the mechanism underlying its sensitization is not fully understood. Here, we report that TNF-mediated sensitization of cancer cells to chemotherapy involves activation of the TRAIL pathway. We show that the combined treatment of breast cancer cells with TNF and Adriamycin significantly increases cell death compared with the treatment with either agent alone. The combined treatment activated both death receptor and mitochondrial apoptotic pathways, whereas Adriamycin alone activated only the mitochondrial pathway, and TNF failed to activate either. Furthermore, we show that TNF induces TRAIL through a transcriptional mechanism. Using reporter gene assays in conjunction with chromatin immunoprecipitation assays, we show that TRAIL induction by TNF is regulated via both nuclear factor-B and Sp1 binding sites. Importantly, down-regulation of TRAIL by small interfering RNA silencing decreased TNF-mediated Adriamycin-induced caspase activation and apoptosis, and thus enhanced breast cancer cell resistance to Adriamycin. Collectively, our results suggest that induction of TRAIL by TNF is critical for sensitization of breast cancer cells to chemotherapy. (Cancer Res 2006; 66(20): 10092-9)

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