Exportin-1 is critical for cell proliferation and survival in adult T cell leukemia

Abstract

Since treatment options for adult T cell leukemia (ATL) associated with human T cell leukemia virus type 1 (HTLV-1) fail to obtain long-term response, novel therapies targeting ATL-dysregulated pathways are necessary. Dysregulated nuclear import and export machinery is common in malignancies. This study aimed to investigate the potential of exportin-1 (XPO1), which mediates nuclear export of cargos, as a target in ATL. RT-PCR and western blotting were performed to determine XPO1 expression. We evaluated XPO1's effects on cell proliferation and viability through WST-8 assays, cell cycle and apoptosis via Hoechst 33342 staining and flow cytometry, and intracellular signaling cascades using western blotting. XPO1 expression was upregulated in HTLV-1-infected T cells. XPO1 knockdown reduced cell proliferation. XPO1 inhibitor KPT-330 also reduced proliferation, increased DNA damage, and induced G1 cell cycle arrest and caspase-dependent apoptosis. KPT-330 downregulated cell cycle regulators (CDK2/4/6, cyclin D2, c-Myc and phosphorylated pRb) and anti-apoptotic proteins (XIAP, c-IAP1/2, survivin and Mcl-1), and upregulated p53, p21 and Bak. KPT-330 suppressed XPO1 and increased the nuclear localization of cargos (NF-κB RelA and its negative regulator IκBα, protein phosphatase 2A and its inhibitor SET, p53 and its negative regulator MDM2, p21, p27, FOXO1 and pRb). KPT-330 treatment resulted in the abrogation of aberrant pathways (NF-κB, Akt and STAT3/5) simultaneously through the activation of tumor suppressor proteins and inhibition of oncogenes and proliferative/survival factors. These findings encourage investigating the use of KPT-330 in clinical trials targeting ATL.

Keywords: Adult T cell leukemia; Akt; Exportin-1; Human T cell leukemia virus type 1; NF-κB; STATs.