Abstract
In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression.
Highlights
Nuclear factor kappaB (NF-kB) is a transcription factor that regulates immune and antiapoptotic responses to multiple extracellular stresses.1,2 Under normal conditions, most NF-kB molecules are sequestered in the cytoplasm by the inhibitor I kB
As we previously demonstrated that the expression of Tax resulted in the formation of a high molecular weight (HMW)-I kB kinase (IKK) complex for activating NF-kB,11 we speculated that the inhibition of heat-shock protein 90 (HSP90) function by GA would affect Tax-mediated NF-kB signaling
As our current study shows the involvement of HSP90 in Tax-mediated HMW-IKK formation and NF-kB activation,11,17 we generated Flag-tagged serial deletion mutants of
Summary
Nuclear factor kappaB (NF-kB) is a transcription factor that regulates immune and antiapoptotic responses to multiple extracellular stresses. Under normal conditions, most NF-kB molecules are sequestered in the cytoplasm by the inhibitor I kB. In contrast to the TNF-a-triggered canonical pathway, which is transient and mostly IKKb dependent, Tax-mediated NF-kB activation is persistent and utilizes both the IKKa and IKKb subunits.20,21 From these observations, we speculated that oncogenic Tax-mediated activation of NF-kB is distinguishable from the canonical NF-kB activation pathway, and we have succeeded in inhibiting Tax-mediated NF-kB activation using selected sets of NEMO-mutant peptides.. We treated ATL cell lines or HEK293 cells transfected with a Tax expression vector with GA or its less toxic derivative 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG).. We treated ATL cell lines or HEK293 cells transfected with a Tax expression vector with GA or its less toxic derivative 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG).22 (huNOG) mice inoculated with HTLV-1-producing Jurkat cells resulted in the suppression of de novo viral production and improved the survival period
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