Targeting autophagic regulation of NFkappaB in HTLV-I transformed cells by geldanamycin: implications for therapeutic interventions.
The IkappaB kinase (IKK)/NFkappaB 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 NFkappaB 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 NFkappaB-inducing kinase (NIK), an upstream kinase of IKK, and inactivation of NFkappaB in various cell lines. Here, we further report that GA inhibition of Hsp90 also led to IKK autophagic degradation and NFkappaB 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 NFkappaB activation by targeting autophagic degradation of the central NFkappaB activating kinases.
Yan
Pengrong
P
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey, USA.
Qing
Guoliang
G
Qu
Zhaoxia
Z
Wu
Chang-Chih
CC
Rabson
Arnold
A
Xiao
Gutian
G
D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones / Q000627:therapeutic use*; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; C001277:geldanamycin