Importin Beta 1 Regulates Cell Growth And Survival During Adult T Cell Leukemia/Lymphoma Therapy

There is no cure for adult T cell leukemia/lymphoma (ATLL) associated with human T cell leukemia virus type 1 (HTLV-1), and novel targeted strategies are needed. NF-kappa B and AP-1 are crucial for ATLL, and both are transported to the nucleus by an importin (IPO)alpha/beta heterodimeric complex to activate target genes. In this study, we aimed to elucidate the function of IPO beta 1 in ATLL. The expression of IPO beta 1 was analyzed by western blotting and RT-PCR. Cell growth, viability, cell cycle, apoptosis and intracellular signaling cascades were examined by the water-soluble tetrazolium-8 assay, flow cytometry and western blotting. Xenograft tumors in severe combined immune deficient mice were used to evaluate the growth of ATLL cells in vivo. IPO beta 1 was upregulated in HTLV-1-infected T cell lines. Further, IPO beta 1 knockdown or the IPO beta 1 inhibitor importazole and the IPO alpha/beta 1 inhibitor ivermectin reduced HTLV-1-infected T cell proliferation. However, the effect of inhibitors on uninfected T cells was less pronounced. Further, in HTLV-1-infected T cell lines, inhibitors suppressed NF-kappa B and AP-1 nuclear transport and DNA binding, induced apoptosis and poly (ADP-ribose) polymerase cleavage, and activated caspase-3, caspase-8 and caspase-9. Inhibitors also mediated G(1)cell cycle arrest. Moreover, the expression of NF-kappa B- and AP-1-target proteins involved in cell cycle and apoptosis was reduced. In vivo, the IPO alpha/beta 1 inhibitor ivermectin decreased ATLL tumor burden without side effects. IPO beta 1 mediated NF-kappa B and AP-1 translocation into ATLL cell nuclei, thereby regulating cell growth and survival, which provides new insights for targeted ATLL therapies. Thus, ivermectin, an anti-strongyloidiasis medication, could be a potent anti-ATLL agent.