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.