Targeting autophagic regulation of NFκB in HTLV-I transformed cells by geldanamycin -: Implications for therapeutic interventions

The I kappa B kinase (IKK)/NF kappa B signaling pathway plays an essential role in the development and survival of many types of cancers including adult Tcell leukemia (ATL) caused by the human Tcell leukemia virus type I (HTLV-I) infection. Accordingly, targeting NF kappa B 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 kappa B-inducing kinase (NIK), an upstream kinase of IKK, and inactivation of NF kappa B in various cell lines. Here, we further report that GA inhibition of Hsp90 also led to IKK autophagic degradation and NF kappa B 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 kappa B activation by targeting autophagic degradation of the central NF kappa B activating kinases.