Journal Article

Mitotic kinase PBK/TOPK as a therapeutic target for adult T-cell leukemia/lymphoma

Mori, Naoki, Senba, Masachika, Ishikawa, Chie

2018

Overview

Adult T-cell leukemia/lymphoma (ATLL) is a disorder involving human T-cell leukemia virus type 1 (HTLV-1)-infected T-cells characterized by increased clonal neoplastic proliferation. PDZ-binding kinase (PBK) [also known as T-lymphokine-activated killer cell-originated protein kinase (TOPK)] is a serine/threonine kinase expressed in proliferative cells and is phosphorylated during mitosis. In this study, the expression and phosphorylation of PBK/TOPK were examined by western blot analysis and RT-PCR. We found that PBK/TOPK was upregulated and phosphory-lated in HTLV-1-transformed T-cell lines and ATLL-derived T-cell lines. Notably, CDK1/cyclin B1, which phosphorylates PBK/TOPK, was overexpressed in these cells. HTLV-1 infection upregulated PBK/TOPK expression in peripheral blood mononuclear cells (PBMCs) in co-culture assays. The potent PBK/TOPK inhibitors, HI-TOPK-032, and fucoidan from brown algae, decreased the proliferation and viability of these cell lines in a dose-dependent manner. By contrast, the effect of HI-TOPK-032 on PBMCs was less pronounced. Treatment with HI-TOPK-032 resulted in G1 cell cycle arrest, and decreased CDK6 expression and pRb phosphorylation, which are critical determinants of progression through the G1 phase. In addition, HI-TOPK-032 induced apoptosis, as evidenced by morphological changes, the cleavage of poly(ADP-ribose) polymerase with the activation of caspase−3, −8 and −9, and an increase in the sub-G1 cell population and APO2.7-positive cells. Moreover, HI-TOPK-032 inhibited the expression of cellular inhibitor of apoptosis 2 (c-IAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin and myeloid cell leukemia-1 (Mcl-1), and induced the expression of Bak and interferon-induced protein with tetratricopeptide repeats (IFIT)1, 2 and 3. It is noteworthy that the use of this inhibitor led to the inhibition of the phosphorylation of IκB kinase (IKK)α, IKKβ, IκBα, phosphatase and tensin homolog (PTEN) and Akt, and to the decreased protein expression of JunB and JunD, suggesting that PBK/TOPK affects the nuclear factor-κB, Akt and activator protein-1 signaling pathways. In vivo, the administration of HI-TOPK-032 suppressed tumor growth in an ATLL xenograft model. Thus, on the whole, this study on the identification and functional analysis of PBK/TOPK suggests that this kinase is a promising molecular target for ATLL treatment.

• Publisher: D.A. Spandidos,Spandidos Publications,Spandidos Publications UK Ltd
• Subject: activator protein-1 / adult T-cell leukemia/lymphoma / Akt / Apoptosis / Cancer therapies / Care and treatment / Cell cycle / Development and progression / Genetic aspects / Health aspects / human T-cell leukemia virus type 1 / Immunoglobulins / Innovations / interferon-induced protein with tetratricopeptide repeats / Kinases / Laboratories / Leukemia / Lymphoma / Medical prognosis / Molecular targeted therapy / nuclear factor-κB / PDZ-binding kinase/T-lymphokine-activated killer cell-originated protein kinase / Phosphotransferases / Proteins / Tumors