Role of Nek2 and Hec1 in HTLV-1-Infected T-Cell Lines.

[OBJECTIVES] Adult T-cell leukemia (ATL), caused by human T-cell leukemia virus type 1 (HTLV-1), has a poorer prognosis than other peripheral T-cell lymphomas. Phosphorylation of highly expressed in cancer 1 (Hec1) by NIMA-related kinase 2 (Nek2) is essential for mitosis. This study evaluated the therapeutic potential of Nek2 and Hec1 inhibitors in ATL.

[METHODS] Cell proliferation, survival, cell cycle progression, apoptosis, mitochondrial membrane potential, and reactive oxygen species (ROS) were assessed. Expression of Nek2, Hec1, and related signaling proteins was also analyzed.

[RESULTS] Nek2 and Hec1 were upregulated in HTLV-1-infected T-cell lines and in normal peripheral blood mononuclear cells after infection. Knockdown of Nek2 or treatment with Nek2/Hec1 inhibitors (INH154, T-1101 tosylate) or the Nek2 inhibitor MBM-55S reduced proliferation and survival. INH154 induced Nek2 degradation and G1-phase arrest, accompanied by downregulation of CDK2/4, cyclin D2/E, c-Myc, and phospho-pRb, and upregulation of p53. It also triggered apoptosis via caspase activation, downregulation of Mcl-1, survivin, and c-IAP2, and upregulation of Bax and Bak. Additionally, INH154 induced necroptosis, ROS accumulation, DNA damage, mitochondrial dysfunction, and suppression of β-catenin and NF-κB/AP-1 signaling.

[CONCLUSION] Aberrant expression of Nek2 and Hec1 may contribute to ATL pathogenesis.