TOPK Activation Exerts Protective Effects on Cisplatin-induced Acute Kidney Injury

Abstract

Objective

T-LAK-cell-originated protein kinase (TOPK), a PSD95-Disc large-ZO1 (PDZ) binding kinase (PBK), is a novel member of the mitogen-activated protein kinase (MAPK) family. Studies have shown that TOPK plays a critical role in the function of tumor cells, including apoptosis and mitosis. However, little is known on the effect of TOPK in cisplatin-induced acute kidney injury (CP-AKI). This study aimed to investigate the role and mechanism of TOPK in CP-AKI.

Methods

Cisplatin was administered to C57BL/6 mice and cultured kidney tubular epithelial cells (TECs) to establish the CP-AKI murine or cellular models. TECs were then stimulated with the specific inhibitor of TOPK OTS514 or transfected with the recombinant-activated plasmid TOPK-T9E to inhibit or activate TOPK. The TECs were treated with AKT inhibitor VIII following stimulation with OTS514 or cisplatin. Western blotting and flow cytometry were used to evaluate the cell cycle and apoptosis of TECs.

Results

The analysis revealed that the TOPK activity was significantly suppressed by cisplatin, both in vivo and in vitro. Furthermore, the pharmacological inhibition of TOPK by OTS514, a specific inhibitor of TOPK, exacerbated the cisplatin-induced cell cycle arrest in the G2/M phase and apoptosis of cultured TECs. Moreover, the TOPK activation via the TOPK-T9E plasmid transfection could partially reverse the cell cycle arrest at the G2/M phase and apoptosis of cisplatin-treated TECs. In addition, AKT/protein kinase B (PKB), as a TOPK target protein, was inhibited by cisplatin in cultured TECs. The pharmaceutical inhibition of AKT further aggravated the apoptosis of TECs induced by cisplatin or TOPK inhibition. TOPK systematically mediated the apoptosis via the AKT pathway in the CP-AKI cell model.

Conclusion

These results indicate that TOPK activation protects against CP-AKI by ameliorating the G2/M cell cycle arrest and cell apoptosis.

Keywords

acute kidney injury / cisplatin / cell cycle / apoptosis / T-LAK-cell-originated protein kinase/PSD95-Disc large-ZO1 binding kinase

References

[1] StrauchJT, SchernerMP, HaldenwangPL, et al.. Minimally invasive transapical aortic valve implantation and the risk of acute kidney injury. Ann Thorac Surg, 2010, 89(2): 465-470

[2] FillastreJP, Raguenez-ViotteG. Cisplatin nephrotoxicity. Toxicol Lett, 1989, 46(1–3): 163-175

[3] GaoZ, ChenX, FanY, et al.. Sirt6 attenuates hypoxia-induced tubular epithelial cell injury via targeting G2/M phase arrest. J Cell Physiol, 2020, 235(4): 3463-3473

[4] FiorentinoM, GrandalianoG, GesualdoL, et al.. Acute Kidney Injury to Chronic Kidney Disease Transition. Contrib Nephrol, 2018, 193: 45-54

[5] OzkokA, EdelsteinCL. Pathophysiology of cisplatin-induced acute kidney injury. Biomed Res Int, 2014, 2014: 967826

[6] MakrisK, SpanouL A K. Injury: Definition, Pathophysiology and Clinical Phenotypes. Clin Biochem Rev, 2016, 37(2): 85-98

[7] MatsumotoS, AbeY, FujibuchiT, et al.. Characterization of a MAPKK-like protein kinase TOPK. Biochem Biophys Res Commun, 2004, 325(3): 997-1004

[8] FujibuchiT, AbeY, TakeuchiT, et al.. Expression and phosphorylation of TOPK during spermatogenesis. Dev Growth Differ, 2005, 47(9): 637-644

[9] WeiDC, YehYC, HungJJ, et al.. Overexpression of T-LAK cell-originated protein kinase predicts poor prognosis in patients with stage I lung adenocarcinoma. Cancer Sci, 2012, 103(4): 731-738

[10] VishchukOS, SunH, WangZ, et al.. PDZ-bmdmg 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, 2016, 7(14): 18763-18773

[11] LuH, XiaoJ, KeC, et al.. TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ. Cell Death Dis, 2019, 10(8): 583

[12] FanX, DuanQ, KeC, et al.. Cefradine blocks solar-ultraviolet induced skin inflammation through direct inhibition of T-LAK cell-originated protein kinase. Oncotarget, 2016, 7(17): 24633-24645

[13] LiuY, LiuH, CaoH, et al.. PBK/TOPK mediates promyelocyte proliferation via Nrf2-regulated cell cycle progression and apoptosis. Oncol Rep, 2015, 34(6): 3288-3296

[14] ParkJH, ParkSA, LeeYJ, et al.. TOPK inhibition accelerates oxidative stress-induced granulosa cell apoptosis via the p53/SIRT1 axis. Int J Mol Med, 2020, 46(5): 1923-1937

[15] GaoS, ZhuY, LiH, et al.. Remote ischemic postconditioning protects against renal ischemia/reperfusion injury by activation of T-LAK-cell-originated protein kinase (TOPK)/PTEN/Akt signaling pathway mediated anti-oxidation and anti-inflammation. Int Immunopharmacol, 2016, 38: 395-401

[16] NettuwakulC, SawasdeeN, PraditsapO, et al.. A novel loss-of-function mutation of PBK associated with human kidney stone disease. Sci Rep, 2020, 10(1): 10282

[17] TsuruyaK, NinomiyaT, TokumotoM, et al.. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int, 2003, 63(1): 72-82

[18] KimYJ, KimTW, ParkSR, et al.. Expression of the Mre11-Rad50-Nbs1 complex in cisplatin nephrotoxicity. Environ Toxicol Pharmacol, 2015, 40(1): 12-17

[19] ZhaoR, HuangH, ChoiBY, et al.. Cell growth inhibition by 3-deoxysappanchalcone is mediated by directly targeting the TOPK signaling pathway in colon cancer. Phytomedicine, 2019, 61: 152813

[20] ShihMC, ChenJY, WuYC, et al.. TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer. Oncogene, 2012, 31(19): 2389-2400

[21] ChaiY, ZhuK, LiC, et al.. Dexmedetomidine alleviates cisplatin-induced acute kidney injury by attenuating endoplasmic reticulum stress-induced apoptosis via the α2AR/PI3K/AKT pathway. Mol Med Rep, 2020, 21(3): 1597-1605

[22] DengF, SharmaI, DaiY, et al.. Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule. J Clin Invest, 2019, 129(11): 5033-5049

[23] MolitorisBA, DagherPC, SandovalRM, et al.. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury. J Am Soc Nephrol, 2009, 20(8): 1754-1764

[24] JiangMH, CaiB, TuoY, et al.. Characterization of Nestin-positive stem Leydig cells as a potential source for the treatment of testicular Leydig cell dysfunction. Cell Res, 2014, 24(12): 1466-1485

[25] HanWK, BaillyV, AbichandaniR, et al.. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int, 2002, 62(1): 237-244

[26] MunshiR, JohnsonA, SiewED, et al.. MCP-1 gene activation marks acute kidney injury. J Am Soc Nephrol, 2011, 22(1): 165-175

[27] XuJ, YuX, MartinTC, et al.. AKT Degradation Selectively Inhibits the Growth of PI3K/PTEN Pathway-Mutant Cancers with Wild-Type KRAS and BRAF by Destabilizing Aurora Kinase B. Cancer Discov, 2021, 11(12): 3064-3089

[28] KarA, ZhangY, YacobBW, et al.. Targeting PDZ-binding kinase is anti-tumorigenic in novel preclinical models of ACC. Endocr Relat Cancer, 2019, 26(10): 765-778

[29] Brown-ClayJD, ShenoyDN, TimofeevaO, et al.. PBK/TOPK enhances aggressive phenotype in prostate cancer via β-catenin-TCF/LEF-mediated matrix metalloproteinases production and invasion. Oncotarget, 2015, 6(17): 15594-15609

[30] HashiguchiY, TsudaH, NishimuraS, et al.. Relationship between HPV typing and the status of G2 cell cycle regulators in cervical neoplasia. Oncol Rep, 2004, 12(3): 587-591

[31] LiuJ, LiuY, XieT, et al.. Radiation-induced G2/M arrest rarely occurred in glioblastoma stem-like cells. Int J Radiat Biol, 2018, 94(4): 394-402

[32] LuoQ, GuoH, KuangP, et al.. Sodium Fluoride Arrests Renal G2/M Phase Cell-Cycle Progression by Activating ATM-Chk2-P53/Cdc25C Signaling Pathway in Mice. Cell Physiol Biochem, 2018, 51(5): 2421-2433

[33] MaZ, WeiQ, DongG, et al.. DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells. Biochim Biophys Acta, 2014, 1842(7): 1088-1096

[34] YangL, BesschetnovaTY, BrooksCR, et al.. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med, 2010, 16(5): 535-543

[35] GerhardtLMS, LiuJ, KoppitchK, et al.. Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury. Proc Natl Acad Sci U S A, 2021, 118(27): e2026684118

[36] TeradaY. Aurora-B/AIM-1 regulates the dynamic behavior of HP1alpha at the G2-M transition. Mol Biol Cell, 2006, 17(7): 3232-3241

[37] WangX, SinnAL, PollokK, et al.. Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma. Br J Haematol, 2010, 150(3): 313-325

[38] Ah-CannC, WimmerVC, WeedenCE, et al.. A functional genetic screen identifies aurora kinase b as an essential regulator of Sox9-positive mouse embryonic lung progenitor cells. Development, 2021, 148(13): dev199543

[39] HuF, GartenhausRB, EichbergD, et al.. PBK/TOPK interacts with the DBD domain of tumor suppressor p53 and modulates expression of transcriptional targets including p21. Oncogene, 2010, 29(40): 5464-5474

[40] TakedaT, TsubakiM, GennoS, et al.. AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitorsensitive and -resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B. Oncol Rep, 2020, 44(5): 2211-2218

[41] LiM, LiuH, ZhaoQ, et al.. Targeting Aurora B kinase with Tanshinone IIA suppresses tumor growth and overcomes radioresistance. Cell Death Dis, 2021, 12(2): 152

[42] XieCM, LinXT, WuD, et al.. Cardiac glycoside bufalin blocks cancer cell growth by inhibition of Aurora A and Aurora B activation via PI3K-Akt pathway. Oncotarget, 2018, 9(17): 13783-13795

[43] ZhouLD, XiongX, LongXH, et al.. RNA interference-mediated knockdown of Aurora-B alters the metastatic behavior of A549 cells via modulation of the phosphoinositide 3-kinase/Akt signaling pathway. Oncol Lett, 2014, 8(5): 2063-2068

[44] ZhuLB, JiangJ, ZhuXP, et al.. Knockdown of Aurora-B inhibits osteosarcoma cell invasion and migration via modulating PI3K/Akt/NF-κB signaling pathway. Int J Clin Exp Pathol, 2014, 7(7): 3984-3991

[45] ZhouYD, HouJG, YangG, et al.. Icariin ameliorates cisplatin-induced cytotoxicity in human embryonic kidney 293 cells by suppressing ROS-mediated PI3K/Akt pathway. Biomed Pharmacother, 2019, 109: 2309-2317