The IκappaB kinase (IKK)/NF-κappaB signaling pathway plays an essential role in the development and survival of many types of cancers including adult T-cell leukemia (ATL) caused by the human T-cell leukemia virus type I (HTLV-I) infection. Accordingly, targeting NF-κappaB provides an attractive strategy for cancer therapy. We recently found that specific inhibition of Hsp90 by geldanamycin (GA) results in autophagic degradation of IKK and NF-κappaB-inducing kinase (NIK), an upstream kinase of IKK, and inactivation of NF-κappaB in various cell lines. Here, we further report that GA inhibition of Hsp90 also led to IKK autophagic degradation and NF-κappaB inhibition in both HTLV-transformed T cells and ATL-derived cell lines. Importantly, GA treatment led to efficient apoptosis of these malignant cells, whereas inhibition of autophagic degradation of IKK significantly ameliorated the cytotoxic effect of GA. These findings thus not only provide mechanistic insights into the tumor suppression function of autophagy and the anti-tumor activity of GA, but also suggest an immediate therapeutic strategy for ATL and other diseases associated with NF-κappaB activation by targeting autophagic degradation of the central NF-kappaB activating kinases.Addendum to:Hsp90 Inhibition Results in Autophagy-Mediated Proteasome-Independent Degradation of IκappaB Kinase (IKK)G. Qing, P. Yan and G. XiaoCell Res 2006; 16:895-901andHsp90 Regulates Processing of NF-κappaB2 p100 Involving Protection of NF-κappaB-Inducing Kinase (NIK) from Autophagy-Mediated DegradationG. Qing, P. Yan, Z. Qu, H. Liu and G. XiaoCell Res 2007; 17:520-30