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

Abstract

Tumor necrosis factor alpha (TNFalpha) induces apoptosis and sensitizes cancer cells to chemotherapy, but the mechanism underlying its sensitization is not fully understood. Here, we report that TNFalpha-mediated sensitization of cancer cells to chemotherapy involves activation of the TRAIL pathway. We show that the combined treatment of breast cancer cells with TNFalpha 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 TNFalpha failed to activate either. Furthermore, we show that TNFalpha induces TRAIL through a transcriptional mechanism. Using reporter gene assays in conjunction with chromatin immunoprecipitation assays, we show that TRAIL induction by TNFalpha is regulated via both nuclear factor-kappaB and Sp1 binding sites. Importantly, down-regulation of TRAIL by small interfering RNA silencing decreased TNFalpha-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 TNFalpha is critical for sensitization of breast cancer cells to chemotherapy.