Tousled-like kinase 1: a novel factor with multifaceted role in mCRPC progression and development of therapy resistance

Abstract

Standard treatment for advanced Prostate Cancer (PCa) consists of androgen deprivation therapy (ADT), but ultimately fails, resulting in the incurable phase of the disease: metastatic castration-resistant prostate cancer (mCRPC). Targeting PCa cells before their progression to mCRPC would greatly improve the outcome, if strategies could be devised selectively targeting androgen receptor (AR)-dependent and/or independent compensatory pathways which promote mCRPC development. Combination therapy by targeting the DNA damage response (DDR) along with ADT has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. In recent years, our lab has identified a key role for the DDR kinase, TLK1, in mediating key aspects of adaptation to ADT, first by promoting a cell cycle arrest (through the TLK1>NEK1>ATR>Chk1 kinase cascade) under the unfavorable growth conditions (androgen deprivation), and then by reprogramming the PCa cells to adapt to androgen-independent growth via the NEK1>YAP/AR>CRPC conversion. In addition, TLK1 plays a key anti-apoptotic role via the NEK1>VDAC1 regulation on the intrinsic mitochondrial apoptotic pathway when the DDR is activated. Finally, TLK1 was recently identified as having an important role in motility and metastasis via regulation of the kinases MK5/PRAK and AKT (indirectly via AKTIP).

Keywords

TLK1 / NEK1 / YAP1 / VDAC1 / DNA damage response / prostate cancer / metastatic castration-resistant prostate cancer / drug resistance in mCRPC

References

[1] Siegel RL,Jemal A.Cancer statistics, 2019.CA A Cancer J Clin2018;69:7-34

[2] Siegel RL,Jemal A.Cancer statistics, 2020.CA Cancer J Clin2020;70:7-30

[3] Siegel RL,Fuchs HE.Cancer statistics, 2021.CA Cancer J Clin2021;71:7-33

[4] Fizazi K,Tammela TL.ARAMIS InvestigatorsDarolutamide in nonmetastatic, castration-resistant prostate cancer.N Engl J Med2019;380:1235-46

[5] Zhang W,Incrocci L,Nonnekens J.Role of the DNA damage response in prostate cancer formation, progression and treatment.Prostate Cancer Prostatic Dis2020;23:24-37 PMCID:PMC8076026

[6] Banks P,Murphy D,Sandhu S.Relevance of DNA damage repair in the management of prostate cancer.Curr Probl Cancer2017;41:287-301

[7] Goodwin JF,Dean JL.A hormone-DNA repair circuit governs the response to genotoxic insult.Cancer Discov2013;3:1254-71 PMCID:PMC3823813

[8] Li L,Yang G.Androgen receptor inhibitor-induced "BRCAness" and PARP inhibition are synthetically lethal for castration-resistant prostate cancer.Sci Signal2017;10:eaam7479 PMCID:PMC5855082

[9] Polkinghorn WR,Lee MX.Androgen receptor signaling regulates DNA repair in prostate cancers.Cancer Discov2013;3:1245-53 PMCID:PMC3888815

[10] Chandrasekar T,Gao AC.Mechanisms of resistance in castration-resistant prostate cancer (CRPC).Transl Androl Urol2015;4:365-80 PMCID:PMC4708226

[11] Zhu ML.Androgen receptor and growth factor signaling cross-talk in prostate cancer cells.Endocr Relat Cancer2008;15:841-9 PMCID:PMC2740735

[12] Craft N,Carey M.A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase.Nat Med1999;5:280-5

[13] Seruga B,Tannock IF.Drug resistance in metastatic castration-resistant prostate cancer.Nat Rev Clin Oncol2011;8:12-23

[14] Silljé HH,Tanaka K,Nigg EA.Mammalian homologues of the plant tousled gene code for cell-cycle-regulated kinases with maximal activities linked to ongoing DNA replication.EMBO J1999;18:5691-702 PMCID:PMC1171636

[15] De Benedetti A. The tousled-like kinases as guardians of genome integrity.ISRN Mol Biol2012;2012:627596 PMCID:PMC3712517

[16] Segura-Bayona S.The tousled-like kinases regulate genome and epigenome stability: implications in development and disease.Cell Mol Life Sci2019;76:3827-41.

[17] Sunavala-Dossabhoy G.Preserving salivary gland physiology against genotoxic damage - the tousled way.Oral Dis2018;24:1390-8. PMCID:PMC6066457

[18] Li Y,Anthony C,De Benedetti A.A translationally regulated tousled kinase phosphorylates histone H3 and confers radioresistance when overexpressed.Oncogene2001;20:726-38

[19] Mortuza GB,Pedersen AK.Molecular basis of tousled-Like Kinase 2 activation.Nat Commun2018;9:2535 PMCID:PMC6023931

[20] Sunavala-Dossabhoy G,De Benedetti A.Translation of the radioresistance kinase TLK1B is induced by gamma-irradiation through activation of mTOR and phosphorylation of 4E-BP1.BMC Mol Biol2004;5:1 PMCID:PMC406498

[21] Norton KS,Sen S.TLK1B is elevated with eIF4E overexpression in breast cancer.J Surg Res2004;116:98-103

[22] Sunavala-Dossabhoy G,Williams B.A dominant negative mutant of TLK1 causes chromosome missegregation and aneuploidy in normal breast epithelial cells.BMC Cell Biol2003;4:16 PMCID:PMC270066

[23] Klimovskaia IM,Strømme CB.Tousled-like kinases phosphorylate Asf1 to promote histone supply during DNA replication.Nat Commun2014;5:3394 PMCID:PMC3977046

[24] Sunavala-Dossabhoy G,Sen S,De Benedetti A.The radioresistance kinase TLK1B protects the cells by promoting repair of double strand breaks.BMC Mol Biol2005;6:19 PMCID:PMC1242231

[25] Sunavala-Dossabhoy G.Tousled homolog, TLK1, binds and phosphorylates Rad9; TLK1 acts as a molecular chaperone in DNA repair.DNA Repair (Amst)2009;8:87-102

[26] Awate S.TLK1B mediated phosphorylation of Rad9 regulates its nuclear/cytoplasmic localization and cell cycle checkpoint.BMC Mol Biol2016;17:3 PMCID:PMC4746922

[27] Singh V,Shen X.Identification of the proteome complement of humanTLK1 reveals it binds and phosphorylates NEK1 regulating its activity.Cell Cycle2017;16:915-26 PMCID:PMC5462085

[28] Jiang J,Zhao Z.Key regulators in prostate cancer identified by co-expression module analysis.BMC Genomics2014;15:1015 PMCID:PMC4258300

[29] Khalil MI,King J.TLK1-MK5 axis drives prostate cancer cell motility and pathologic features of aggressiveness.Res Sq2021;

[30] Singh V,Ghosh I,Yu X.Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors.Int J Cancer2019;145:1055-67 PMCID:PMC6617729

[31] Singh V,Ghosh I,Yu X.The TLK1-Nek1 axis promotes prostate cancer progression.Cancer Lett2019;453:131-41

[32] Carver BS,Wongvipat J.Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.Cancer Cell2011;19:575-86 PMCID:PMC3142785

[33] Mulholland DJ,Li Y.Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth.Cancer Cell2011;19:792-804 PMCID:PMC3157296

[34] Pei H,Fridley BL.FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt.Cancer Cell2009;16:259-66 PMCID:PMC2755578

[35] Magee JA,Stormo GD.Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element.Endocrinology2006;147:590-8

[36] Hausch F,Theodoropoulou M.FKBPs and the Akt/mTOR pathway.Cell Cycle2013;12:2366-70 PMCID:PMC3841315

[37] Polci R,Chen PL,Chen Y.NIMA-related protein kinase 1 is involved early in the ionizing radiation-induced DNA damage response.Cancer Res2004;64:8800-3

[38] Chen Y,Chen CF,Riley DJ.Never-in-mitosis related kinase 1 functions in DNA damage response and checkpoint control.Cell Cycle2008;7:3194-201 PMCID:PMC2597191

[39] Liu S,Ouyang J.Nek1 kinase associates with ATR-ATRIP and primes ATR for efficient DNA damage signaling.Proc Natl Acad Sci U S A2013;110:2175-80 PMCID:PMC3568365

[40] Al-Ubaidi FL,Loseva O,Granfors T.Castration therapy results in decreased Ku70 levels in prostate cancer.Clin Cancer Res2013;19:1547-56

[41] Teyssonneau D,Cabart M.Prostate cancer and PARP inhibitors: progress and challenges.J Hematol Oncol2021;14:51 PMCID:PMC8008655

[42] Karanika S,Li L.Targeting DNA damage response in prostate cancer by inhibiting androgen receptor-CDC6-ATR-Chk1 signaling.Cell Rep2017;18:1970-81 PMCID:PMC5349188

[43] Karanika S,Li L,Thompson TC.DNA damage response and prostate cancer: defects, regulation and therapeutic implications.Oncogene2015;34:2815-22 PMCID:PMC4333141

[44] Ronald S,Rath A.Phenothiazine inhibitors of TLKs affect double-strand break repair and DNA damage response recovery and potentiate tumor killing with radiomimetic therapy.Genes Cancer2013;4:39-53 PMCID:PMC3743153

[45] Jin X,Luo L.Codelivery of thioridazine and doxorubicin using nanoparticles for effective breast cancer therapy.Int J Nanomedicine2016;11:4545-52 PMCID:PMC5019472

[46] Ibrahim K,Harun R.Knockdown of tousled-like kinase 1 inhibits survival of glioblastoma multiforme cells.Int J Mol Med2020;46:685-99 PMCID:PMC7307829

[47] Takayama Y,Yokoyama Y.Silencing of tousled-like kinase 1 sensitizes cholangiocarcinoma cells to cisplatin-induced apoptosis.Cancer Lett2010;296:27-34

[48] Rho SB,Kang S.A gene signature-based approach identifies thioridazine as an inhibitor of phosphatidylinositol-3'-kinase (PI3K)/AKT pathway in ovarian cancer cells.Gynecol Oncol2011;120:121-7

[49] Nomura T.Molecular mechanisms of cisplatin resistance in prostate cancer cells. In: Parsons RA, editor. Progress in Cancer Drug Resistance Research. NOVA; 2007; p. 121.

[50] Shu Y,Liang Z.Quercetin reverses the doxorubicin resistance of prostate cancer cells by downregulating the expression of c-met.Oncol Lett2018;15:2252-8 PMCID:PMC5777119

[51] Singh V,Chikhale RV.Generation of phenothiazine with potent anti-TLK1 activity for prostate cancer therapy.iScience2020;23:101474 PMCID:PMC7486443

[52] Khalil MI,Singh V,Zhu H.NEK1 Phosphorylation of YAP promotes its stabilization and transcriptional output.Cancers (Basel)2020;12:3666 PMCID:PMC7762262

[53] Yim H,You J,Benjamin T.Nek1 and TAZ interact to maintain normal levels of polycystin 2.J Am Soc Nephrol2011;22:832-7 PMCID:PMC3269896

[54] Kuser-Abali G,Lewis M,Cinar B.YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat Commun2015;6:8126 PMCID:PMC5327734

[55] Salem O.The hippo pathway in prostate cancer.Cells2019;8:370 PMCID:PMC6523349

[56] Singh V,De Benedetti A.The TLK1/Nek1 axis contributes to mitochondrial integrity and apoptosis prevention via phosphorylation of VDAC1.Cell Cycle2020;19:363-75 PMCID:PMC7028156

[57] Shoshan-Barmatz V.Mitochondrial VDAC1: function in cell life and death and a target for cancer therapy.Curr Med Chem2012;19:714-35

[58] Chen Y,Riley DJ.Nek1 regulates cell death and mitochondrial membrane permeability through phosphorylation of VDAC1.Cell Cycle2009;8:257-67 PMCID:PMC2673983

[59] Khalil MI,Ghosh I,De Benedetti A.Interaction of TLK1 and AKTIP as a potential regulator of AKT activation in castration-resistant prostate cancer progression.Pathophysiology2021;28:339-54