Targeting Autophagic Regulation of NF-kappaB in HTLV-I Transformed Cells by Geldanamycin: Implications for Therapeutic Interventions

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 auto...