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

Ishikawa,Chie; Senba,Masachika; Mori,Naoki

doi:10.3892/ijo.2018.4427

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

Authors:
- Chie Ishikawa
- Masachika Senba
- Naoki Mori
View Affiliations

Affiliations: Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan
Published online on: June 1, 2018 https://doi.org/10.3892/ijo.2018.4427
Pages: 801-814

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Ishitsuka K and Tamura K: Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. Lancet Oncol. 15:e517–e526. 2014. View Article : Google Scholar : PubMed/NCBI
2	Hall WW and Fujii M: Deregulation of cell-signaling pathways in HTLV-1 infection. Oncogene. 24:5965–5975. 2005. View Article : Google Scholar : PubMed/NCBI
3	Mori N: Cell signaling modifiers for molecular targeted therapy in ATLL. Front Biosci. 14:1479–1489. 2009. View Article : Google Scholar
4	Watanabe T: Adult T-cell leukemia: Molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood. 129:1071–1081. 2017. View Article : Google Scholar : PubMed/NCBI
5	Currer R, Van Duyne R, Jaworski E, Guendel I, Sampey G, Das R, Narayanan A and Kashanchi F: HTLV tax: A fascinating multifunctional co-regulator of viral and cellular pathways. Front Microbiol. 3:4062012. View Article : Google Scholar : PubMed/NCBI
6	Abe Y, Matsumoto S, Kito K and Ueda N: Cloning and expression of a novel MAPKK-like protein kinase, lymphokine-activated killer T-cell-originated protein kinase, specifically expressed in the testis and activated lymphoid cells. J Biol Chem. 275:21525–21531. 2000. View Article : Google Scholar : PubMed/NCBI
7	Simons-Evelyn M, Bailey-Dell K, Toretsky JA, Ross DD, Fenton R, Kalvakolanu D and Rapoport AP: PBK/TOPK is a novel mitotic kinase which is upregulated in Burkitt's lymphoma and other highly proliferative malignant cells. Blood Cells Mol Dis. 27:825–829. 2001. View Article : Google Scholar
8	Nandi A, Tidwell M, Karp J and Rapoport AP: Protein expression of PDZ-binding kinase is up-regulated in hematologic malignancies and strongly down-regulated during terminal differentiation of HL-60 leukemic cells. Blood Cells Mol Dis. 32:240–245. 2004. View Article : Google Scholar : PubMed/NCBI
9	Gaudet S, Branton D and Lue RA: Characterization of PDZ-binding kinase, a mitotic kinase. Proc Natl Acad Sci USA. 97:5167–5172. 2000. View Article : Google Scholar : PubMed/NCBI
10	Matsumoto S, Abe Y, Fujibuchi T, Takeuchi T, Kito K, Ueda N, Shigemoto K and Gyo K: Characterization of a MAPKK-like protein kinase TOPK. Biochem Biophys Res Commun. 325:997–1004. 2004. View Article : Google Scholar : PubMed/NCBI
11	Shats I, Gatza ML, Chang JT, Mori S, Wang J, Rich J and Nevins JR: Using a stem cell-based signature to guide therapeutic selection in cancer. Cancer Res. 71:1772–1780. 2011. View Article : Google Scholar :
12	Takeda K, Tomimori K, Kimura R, Ishikawa C, Nowling TK and Mori N: Anti-tumor activity of fucoidan is mediated by nitric oxide released from macrophages. Int J Oncol. 40:251–260. 2012.
13	Tanaka Y, Yoshida A, Takayama Y, Tsujimoto H, Tsujimoto A, Hayami M and Tozawa H: Heterogeneity of antigen molecules recognized by anti-tax1 monoclonal antibody Lt-4 in cell lines bearing human T cell leukemia virus type I and related retroviruses. Jpn J Cancer Res. 81:225–231. 1990. View Article : Google Scholar : PubMed/NCBI
14	Kimura R, Senba M, Cutler SJ, Ralph SJ, Xiao G and Mori N: Human T cell leukemia virus type I tax-induced IκB-ζ modulates tax-dependent and tax-independent gene expression in T cells. Neoplasia. 15:1110–1124. 2013. View Article : Google Scholar : PubMed/NCBI
15	Mori N and Prager D: Transactivation of the interleukin-1alpha promoter by human T-cell leukemia virus type I and type II Tax proteins. Blood. 87:3410–3417. 1996.PubMed/NCBI
16	Inoue J, Seiki M, Taniguchi T, Tsuru S and Yoshida M: Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO J. 5:2883–2888. 1986.PubMed/NCBI
17	Kim DJ, Li Y, Reddy K, Lee M-H, Kim MO, Cho Y-Y, Lee S-Y, Kim J-E, Bode AM and Dong Z: Novel TOPK inhibitor HI-TOPK-032 effectively suppresses colon cancer growth. Cancer Res. 72:3060–3068. 2012. View Article : Google Scholar : PubMed/NCBI
18	Zhang C, Ao Z, Seth A and Schlossman SF: A mitochondrial membrane protein defined by a novel monoclonal antibody is preferentially detected in apoptotic cells. J Immunol. 157:3980–3987. 1996.PubMed/NCBI
19	Iwanaga R, Ozono E, Fujisawa J, Ikeda MA, Okamura N, Huang Y and Ohtani K: Activation of the cyclin D2 and cdk6 genes through NF-kappaB is critical for cell-cycle progression induced by HTLV-I Tax. Oncogene. 27:5635–5642. 2008. View Article : Google Scholar : PubMed/NCBI
20	Kawakami H, Tomita M, Matsuda T, Ohta T, Tanaka Y, Fujii M, Hatano M, Tokuhisa T and Mori N: Transcriptional activation of survivin through the NF-kappaB pathway by human T-cell leukemia virus type I tax. Int J Cancer. 115:967–974. 2005. View Article : Google Scholar : PubMed/NCBI
21	Kawakami A, Nakashima T, Sakai H, Urayama S, Yamasaki S, Hida A, Tsuboi M, Nakamura H, Ida H, Migita K, et al: Inhibition of caspase cascade by HTLV-I tax through induction of NF-kappaB nuclear translocation. Blood. 94:3847–3854. 1999.PubMed/NCBI
22	Wäldele K, Silbermann K, Schneider G, Ruckes T, Cullen BR and Grassmann R: Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes. Blood. 107:4491–4499. 2006. View Article : Google Scholar : PubMed/NCBI
23	Reuter S, Prasad S, Phromnoi K, Ravindran J, Sung B, Yadav VR, Kannappan R, Chaturvedi MM and Aggarwal BB: Thiocolchicoside exhibits anticancer effects through down-regulation of NF-κB pathway and its regulated gene products linked to inflammation and cancer. Cancer Prev Res (Phila). 3:1462–1472. 2010. View Article : Google Scholar
24	Sun S-C and Cesarman E: NF-κB as a target for oncogenic viruses. Curr Top Microbiol Immunol. 349:197–244. 2011.
25	Park J-H, Yoon D-S, Choi H-J, Hahm D-H and Oh S-M: Phosphorylation of IκBα at serine 32 by T-lymphokine-activated killer cell-originated protein kinase is essential for chemoresistance against doxorubicin in cervical cancer cells. J Biol Chem. 288:3585–3593. 2013. View Article : Google Scholar
26	Madrid LV, Mayo MW, Reuther JY and Baldwin AS Jr: Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem. 276:18934–18940. 2001. View Article : Google Scholar : PubMed/NCBI
27	Hollander MC, Blumenthal GM and Dennis PA: PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 11:289–301. 2011. View Article : Google Scholar : PubMed/NCBI
28	Nakahata S, Ichikawa T, Maneesaay P, Saito Y, Nagai K, Tamura T, Manachai N, Yamakawa N, Hamasaki M, Kitabayashi I, et al: Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. Nat Commun. 5:33932014. View Article : Google Scholar : PubMed/NCBI
29	Rahdar M, Inoue T, Meyer T, Zhang J, Vazquez F and Devreotes PN: A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc Natl Acad Sci USA. 106:480–485. 2009. View Article : Google Scholar :
30	Shinde SR, Gangula NR, Kavela S, Pandey V and Maddika S: TOPK and PTEN participate in CHFR mediated mitotic checkpoint. Cell Signal. 25:2511–2517. 2013. View Article : Google Scholar : PubMed/NCBI
31	Cherian MA, Baydoun HH, Al-Saleem J, Shkriabai N, Kvaratskhelia M, Green P and Ratner L: Akt pathway activation by human T-cell leukemia virus type 1 Tax oncoprotein. J Biol Chem. 290:26270–26281. 2015. View Article : Google Scholar : PubMed/NCBI
32	Zhang J-F, Chen Y, Lin G-S, Zhang J-D, Tang W-L, Huang J-H, Chen J-S, Wang X-F and Lin Z-X: High IFIT1 expression predicts improved clinical outcome, and IFIT1 along with MGMT more accurately predicts prognosis in newly diagnosed glioblastoma. Hum Pathol. 52:136–144. 2016. View Article : Google Scholar : PubMed/NCBI
33	Reich NC: A death-promoting role for ISG54/IFIT2. J Interferon Cytokine Res. 33:199–205. 2013. View Article : Google Scholar : PubMed/NCBI
34	Yang Y, Zhou Y, Hou J, Bai C, Li Z, Fan J, Ng IOL, Zhou W, Sun H, Dong Q, et al: Hepatic IFIT3 predicts interferon-α therapeutic response in patients of hepatocellular carcinoma. Hepatology. 66:152–166. 2017. View Article : Google Scholar : PubMed/NCBI
35	Matsuoka M and Green PL: The HBZ gene, a key player in HTLV-1 pathogenesis. Retrovirology. 6:712009. View Article : Google Scholar : PubMed/NCBI
36	Haneji K, Matsuda T, Tomita M, Kawakami H, Ohshiro K, Uchihara JN, Masuda M, Takasu N, Tanaka Y, Ohta T, et al: Fucoidan extracted from Cladosiphon okamuranus Tokida induces apoptosis of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells. Nutr Cancer. 52:189–201. 2005. View Article : Google Scholar : PubMed/NCBI
37	Vishchuk OS, Sun H, Wang Z, Ermakova SP, Xiao J, Lu T, Xue P, Zvyagintseva TN, Xiong H, Shao C, et al: PDZ-binding kinase/T-LAK cell-originated protein kinase is a target of the fucoidan from brown alga Fucus evanescens in the prevention of EGF-induced neoplastic cell transformation and colon cancer growth. Oncotarget. 7:18763–18773. 2016. View Article : Google Scholar : PubMed/NCBI
38	Kamihira S, Atogami S, Sohda H, Momita S, Yamada Y and Tomonaga M: Significance of soluble interleukin-2 receptor levels for evaluation of the progression of adult T-cell leukemia. Cancer. 73:2753–2758. 1994. View Article : Google Scholar : PubMed/NCBI
39	Nishioka C, Takemoto S, Kataoka S, Yamanaka S, Moriki T, Shoda M, Watanabe T and Taguchi H: Serum level of soluble CD30 correlates with the aggressiveness of adult T-cell leukemia/lymphoma. Cancer Sci. 96:810–815. 2005. View Article : Google Scholar : PubMed/NCBI
40	Tanaka H, Fujita N and Tsuruo T: 3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phos-phorylation activates NF-kappaB signaling. J Biol Chem. 280:40965–40973. 2005. View Article : Google Scholar : PubMed/NCBI
41	Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM and Donner DB: NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 401:82–85. 1999. View Article : Google Scholar : PubMed/NCBI
42	Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP-Y and Baldwin AS: Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev. 22:1490–1500. 2008. View Article : Google Scholar : PubMed/NCBI
43	Cahill CM and Rogers JT: Interleukin (IL) 1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway targeting activator protein-1. J Biol Chem. 283:25900–25912. 2008. View Article : Google Scholar : PubMed/NCBI
44	Brown RT, Ades IZ and Nordan RP: An acute phase response factor/NF-kappa B site downstream of the junB gene that mediates responsiveness to interleukin-6 in a murine plasmacytoma. J Biol Chem. 270:31129–31135. 1995. View Article : Google Scholar : PubMed/NCBI
45	Garg AD and Agostinis P: Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses. Immunol Rev. 280:126–148. 2017. View Article : Google Scholar : PubMed/NCBI