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

Abstract

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 phosphorylated 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.

PBK phosphorylates MSL1 to elicit epigenetic modulation of CD276 in nasopharyngeal carcinoma

“…Thus, PBK activates downstream signaling cascades via its phosphorylated substrates and plays an important role in many kinds of cellular processes, including growth, development, apoptosis, and inflammation 36 . Previous studies including our group have highlighted that PBK was required for malignant phenotypes and was associated with poor prognosis of human common cancers, including NPC, oral cancer, breast cancer, colorectal cancer, leukemia and lymphoma, ovarian cancer, lung cancer, and glioma 34,[36][37][38][39][40] . Due to the broad expression of PBK across multiple tumor types, specific inhibitors have been developed to target PBK, including HI-TOPK-032 41 , OTS514/OTS964 42 , and ADA-07 43 , and show high therapeutic potency in the preclinical study.…”

PDZ-Binding Kinase-Dependent Transcriptional Regulation of CCNB2 Promotes Tumorigenesis and Radio-Resistance in Glioblastoma

“…It has been reported that PBK plays a major role in mitotic phosphorylation, regulation of DNA damage repair, tumorigenesis, and therapeutic resistance through various protein phosphorylation reactions [9,10]. Increasing evidence has shown that excessive activation of PBK contributes to tumor proliferation, invasion, as well as treatment failure in a variety of tumor types [[11], [12], [13]]. Recent studies demonstrated that overexpression of PBK was correlated with poor prognosis of hepatocellular carcinoma and promoted migration and invasion of tumor cells through ETV4-uPAR signaling pathway [14].…”

Eupafolin Suppresses Esophagus Cancer Growth by Targeting T-LAK Cell-Originated Protein Kinase

“…It is necessary to find TOPK inhibitors with low toxicity to overcome the side-effect of current TOPK inhibitors (Matsuo et al, 2014; Ishikawa et al, 2018). There were several small molecule compounds from Chinese herbal medicine reported to be an inhibitor of TOPK to reduce the proliferation of tumor cells (Diao et al, 2019; Wang et al, 2019).…”