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.

NIMA‐related kinase 2; adult T‐cell leukemia; highly expressed in cancer 1; human T‐cell leukemia virus type 1.