Regulation and function of the RSK family in colorectal cancer

Abstract

P90 Ribosomal S6 Kinases (RSKs) constitute a class of Serine/Threonine (Ser/Thr) protein kinases and play a critical role as downstream targets in the Raf/MEK/ERK signaling pathway. Gaining insight into the biological function of RSK family proteins, given their functions in various tumors, is vital. The RSK family is involved in the regulation of cellular functions including cell proliferation, motility, invasion, and survival. The RSK family comprises four human isoforms (RSK1, RSK2, RSK3, and RSK4). The activation of RSK protein kinases is mediated through direct phosphorylation by extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphoinositide-dependent kinase 1 (PDK1) after the Ras/MAPK (mitogen-activated protein kinase) pathway is activated. Recent evidence suggests that RSK family proteins promote the onset and metastasis of cancer, leading to the association of the protein expression of these kinases with various cancer types, such as colorectal cancer (CRC), breast cancer, lung cancer, kidney cancer, leukemia, esophageal squamous cell carcinoma, ovarian cancer, glioma, and endometrial cancer. In this review, we summarize the latest research on the RSK family, focusing on its role in patients with CRC, along with associated treatment challenges and limitations. This information enhances our comprehension of the regulation and function of RSK family proteins, highlighting their potential as both clinical biomarkers for diagnosing CRC and targets for molecular therapeutic interventions in the future.

Keywords

Colorectal cancer / RSK / molecular mechanism

References

[1] Siegel RL,Cercek A,Jemal A.Colorectal cancer statistics, 2023.CA Cancer J Clin2023;73:233-54

[2] Yu GH,Wei R.Diabetes and colorectal cancer risk: clinical and therapeutic implications.J Diabetes Res2022;2022:1747326 PMCID:PMC8920658

[3] Poomakkoth N,Abdulrahman N,Mraiche F.p90 ribosomal S6 kinase: a potential therapeutic target in lung cancer.J Transl Med2016;14:14 PMCID:PMC4721001

[4] Carriere A,Blenis J.The RSK factors of activating the Ras/MAPK signaling cascade.Front Biosci2008;13:4258-75

[5] Jones SW,Blenis J,Erikson RL.A Xenopus ribosomal protein S6 kinase has two apparent kinase domains that are each similar to distinct protein kinases.Proc Natl Acad Sci USA1988;85:3377-81 PMCID:PMC280212

[6] Houles T.Defining the role of the RSK isoforms in cancer.Semin Cancer Biol2018;48:53-61

[7] Erikson E.A protein kinase from Xenopus eggs specific for ribosomal protein S6.Proc Natl Acad Sci USA1985;82:742-6 PMCID:PMC397122

[8] Alcorta DA,Sweet LJ,Jones SW.Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase.Mol Cell Biol1989;9:3850-9 PMCID:PMC362446

[9] Moller DE,Tang W,Jakubowski M.Human rsk isoforms: cloning and characterization of tissue-specific expression.Am J Physiol1994;266:C351-9

[10] Yntema HG,Kissing J.A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation.Genomics1999;62:332-43

[11] Deak M,Lucocq LM.Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB.EMBO J1998;17:4426-41 PMCID:PMC1170775

[12] Smith JA,Xu Y,Hecht SM.Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation.Cancer Res2005;65:1027-34

[13] Thakur A,Bollig A.Anti-invasive and antimetastatic activities of ribosomal protein S6 kinase 4 in breast cancer cells.Clin Cancer Res2008;14:4427-36 PMCID:PMC3771666

[14] Abdulrahman N,Poomakkoth N.Inhibition of p90 ribosomal S6 kinase attenuates cell migration and proliferation of the human lung adenocarcinoma through phospho-GSK-3β and osteopontin.Mol Cell Biochem2016;418:21-9

[15] Cai J,Huang F.Low expression of RSK4 predicts poor prognosis in patients with colorectal cancer.Int J Clin Exp Pathol2014;7:4959-70 PMCID:PMC4152057

[16] López-Vicente L,Pons B.Regulation of replicative and stress-induced senescence by RSK4, which is down-regulated in human tumors.Clin Cancer Res2009;15:4546-53

[17] Kang S,Lythgoe K.p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells.J Clin Invest2010;120:1165-77 PMCID:PMC2846050

[18] Bignone PA,Liu Y.RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer.Oncogene2007;26:683-700

[19] Romeo Y,Roux PP.Regulation and function of the RSK family of protein kinases.Biochem J2012;441:553-69

[20] Watanabe D,Okada K,Umezawa Y.FLT3-ITD activates RSK1 to enhance proliferation and survival of AML cells by activating mTORC1 and eIF4B cooperatively with PIM or PI3K and by inhibiting bad and BIM.Cancers2019;11:1827 PMCID:PMC6966435

[21] Jin G,Liu K.Discovery of a novel dual-target inhibitor against RSK1 and MSK2 to suppress growth of human colon cancer.Oncogene2020;39:6733-46

[22] Lin L,Hu K.Role of p90RSK in kidney and other diseases.Int J Mol Sci2019;20:972 PMCID:PMC6412535

[23] Torchiaro E,Olivero M.Peritoneal and hematogenous metastases of ovarian cancer cells are both controlled by the p90RSK through a self-reinforcing cell autonomous mechanism.Oncotarget2016;7:712-28 PMCID:PMC4808028

[24] M Hajj GN,de Bellis B.Aberrant expression of RSK1 characterizes high-grade gliomas with immune infiltration.Mol Oncol2020;14:159-79 PMCID:PMC6944115

[25] Zhao H,Davies EL. The Clinical implications of RSK1-3 in human breast cancer. Anticancer Res 2016;36:1267-74. Avaliable from: https://ar.iiarjournals.org/content/36/3/1267 [Last accessed on 26 Jan]

[26] Li LY,Wang KS.RSK2 protects human breast cancer cells under endoplasmic reticulum stress through activating AMPKα2-mediated autophagy.Oncogene2020;39:6704-18

[27] Lee CJ,Yoo SM.Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway.BMC Cancer2015;15:576 PMCID:PMC4529708

[28] Katsuragawa-Taminishi Y,Kawaji-Kanayama Y.Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B-cell lymphomas.Cancer Sci2023;114:4691-705 PMCID:PMC10728023

[29] van Jaarsveld MT,Boersma AW.The kinase RSK2 modulates the sensitivity of ovarian cancer cells to cisplatin.Eur J Cancer2013;49:345-51

[30] Yao K,Zhang Y.RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth.Proc Natl Acad Sci USA2017;114:12791-6 PMCID:PMC5715759

[31] Kumari A,Liu YJ.mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer.JCI Insight2023;8:e156657 PMCID:PMC10077471

[32] Lin H.A novel homozygous deletion at chromosomal band 6q27 in an ovarian cancer cell line delineates the position of a putative tumor suppressor gene.Cancer Lett2001;173:63-70

[33] Fan L,Yin Z.Ribosomal s6 protein kinase 4: a prognostic factor for renal cell carcinoma.Br J Cancer2013;109:1137-46 PMCID:PMC3778307

[34] Chen L,Jia Q,Li M.RSK4: a new prognostic factor in glioma.Pathol Res Pract2020;216:153020

[35] Pang F,Li M.Ribosomal S6 protein kinase 4 promotes resistance to EZH2 inhibitors in glioblastoma.Cancer Gene Ther2023;30:1636-48

[36] Jiang Y,Ji Y.Aberrant expression of RSK4 in breast cancer and its role in the regulation of tumorigenicity.Int J Mol Med2017;40:883-90

[37] Li A,Liu Y,Du Z.A pilot study of RSK4 expression in patients with human non-small cell lung carcinoma.Ann Clin Lab Sci2018;48:484-9

[38] Ye Q,Jin M.Effect of RSK4 on biological characteristics of colorectal cancer.World J Surg Oncol2018;16:240 PMCID:PMC6303929

[39] Rafiee M,Ayatollahi H.Down-regulation of ribosomal S6 kinase RPS6KA6 in acute myeloid leukemia patients.Cell J2016;18:159-64

[40] Li MY,Han DH.Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma.J Clin Invest2020;130:4301-19 PMCID:PMC7410060

[41] Arechavaleta-Velasco F,Estrada-Moscoso I.Ribosomal S6 kinase 4 (RSK4) expression in ovarian tumors and its regulation by antineoplastic drugs in ovarian cancer cell lines.Med Oncol2016;33:11

[42] Jiang X,Yang C.TBX21 attenuates colorectal cancer progression via an ARHGAP29/RSK/GSK3β dependent manner.Cell Oncol2023;46:1269-83

[43] Yang Q,Ma X,Xie W.Gene expression profile comparison between colorectal cancer and adjacent normal tissues.Oncol Lett2017;14:6071-8 PMCID:PMC5661416

[44] Lara R,Pardo OE.The p90 RSK family members: common functions and isoform specificity.Cancer Res2013;73:5301-8

[45] Davies AH,Hu K.Inhibition of RSK with the novel small-molecule inhibitor LJI308 overcomes chemoresistance by eliminating cancer stem cells.Oncotarget2015;6:20570-7 PMCID:PMC4653026

[46] Zeniou M,Trivier E.Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning.Hum Mol Genet2002;11:2929-40

[47] Dümmler BA,Silber J.Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types.J Biol Chem2005;280:13304-14

[48] Anjum R.The RSK family of kinases: emerging roles in cellular signalling.Nat Rev Mol Cell Biol2008;9:747-58

[49] Smith JA,Malarkey K.Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo.J Biol Chem1999;274:2893-8

[50] MacKenzie SJ,McPhee I,Houslay MD.ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions.J Biol Chem2000;275:16609-17

[51] Roux PP,Blenis J.Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Mol Cell Biol2003;23:4796-804 PMCID:PMC162206

[52] Dimitri CA,MacKeigan JP,Murphy LO.Spatially separate docking sites on ERK2 regulate distinct signaling events in vivo.Curr Biol2005;15:1319-24

[53] Dalby KN,Caudwell FB,Cohen P.Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK.J Biol Chem1998;273:1496-505

[54] Bjørbaek C,Moller DE.Divergent functional roles for p90rsk kinase domains.J Biol Chem1995;270:18848-52

[55] Vik TA.Identification of serine 380 as the major site of autophosphorylation of Xenopus pp90rsk.Biochem Biophys Res Commun1997;235:398-402

[56] Ghoda L,Greene WC.The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaBalpha and stimulates its degradation in vitro.J Biol Chem1997;272:21281-8

[57] Xu S,Hou X.Ribosomal S6 kinase-1 modulates interleukin-1beta-induced persistent activation of NF-kappaB through phosphorylation of IkappaBbeta.Am J Physiol Cell Physiol2006;291:C1336-45

[58] David JP,Bakiri L.Essential role of RSK2 in c-Fos-dependent osteosarcoma development.J Clin Invest2005;115:664-72

[59] Rolfe M,Pratt PF.Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2).Biochem J2005;388:973-84 PMCID:PMC1183479

[60] Hsiao KM,Shih SJ.Evidence that inactive p42 mitogen-activated protein kinase and inactive rsk exist as a heterodimer in vivo.Proc Natl Acad Sci USA1994;91:5480-4 PMCID:PMC44019

[61] Zhao Y,Moller DE.Regulation and interaction of pp90(rsk) isoforms with mitogen-activated protein kinases.J Biol Chem1996;271:29773-9

[62] Calvo N,Martin MJ.RSK activation via ERK modulates human colon cancer cells response to PTHrP.J Mol Endocrinol2017;59:13-27

[63] Clark DE,Smith JA,Weber MJ.The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation.Cancer Res2005;65:3108-16

[64] Méant A,Lavoie G.Proteomic analysis reveals a role for RSK in p120-catenin phosphorylation and melanoma cell-cell adhesion.Mol Cell Proteomics2020;19:50-64 PMCID:PMC6944238

[65] Zhao Y,Weremowicz S,Moller DE.RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation.Mol Cell Biol1995;15:4353-63 PMCID:PMC230675

[66] Peng C,Wen W.Tumor necrosis factor receptor-associated factor family protein 2 is a key mediator of the epidermal growth factor-induced ribosomal S6 kinase 2/cAMP-responsive element-binding protein/Fos protein signaling pathway.J Biol Chem2012;287:25881-92

[67] López-Vicente L,Coch L.RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence.Carcinogenesis2011;32:470-6

[68] Boussemart L,Girault I.eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.Nature2014;513:105-9

[69] Lito P,Solit DB.Tumor adaptation and resistance to RAF inhibitors.Nat Med2013;19:1401-9

[70] Roth AD,Delorenzi M.Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.J Clin Oncol2010;28:466-74

[71] Barras D,Wirapati P.BRAF V600E mutant colorectal cancer subtypes based on gene expression.Clin Cancer Res2017;23:104-15

[72] Boussios S,Moschetta M.The developing story of predictive biomarkers in colorectal cancer.J Pers Med2019;9:12 PMCID:PMC6463186

[73] Sueda T,Kawamoto K.BRAF V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells.Sci Rep2016;6:18949 PMCID:PMC4707439

[74] Morris EJ,Restaino CR.Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.Cancer Discov2013;3:742-50

[75] Sun Y,Wu C,Wang C.RSK inhibitors as potential anticancer agents: discovery, optimization, and challenges.Eur J Med Chem2023;251:115229

[76] Hilinski MK,Clark DE.Analogs of the RSK inhibitor SL0101: optimization of in vitro biological stability.Bioorg Med Chem Lett2012;22:3244-7 PMCID:PMC3331937

[77] Sapkota GP,Newell FS.BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo.Biochem J2007;401:29-38 PMCID:PMC1698666

[78] Pambid MR,Adomat HH.Overcoming resistance to sonic hedgehog inhibition by targeting p90 ribosomal S6 kinase in pediatric medulloblastoma.Pediatr Blood Cancer2014;61:107-15

[79] Aronchik I,Basham SE.Novel potent and selective inhibitors of p90 ribosomal S6 kinase reveal the heterogeneity of RSK function in MAPK-driven cancers.Mol Cancer Res2014;12:803-12

[80] Jain R,Lan J.Discovery of potent and selective RSK inhibitors as biological probes.J Med Chem2015;58:6766-83

[81] Kirrane TM,Burke J.Indole RSK inhibitors. Part 2: optimization of cell potency and kinase selectivity.Bioorg Med Chem Lett2012;22:738-42

[82] Boyer SJ,Guo X.Indole RSK inhibitors. Part 1: discovery and initial SAR.Bioorg Med Chem Lett2012;22:733-7

[83] Cohen MS,Shokat KM.Structural bioinformatics-based design of selective, irreversible kinase inhibitors.Science2005;308:1318-21 PMCID:PMC3641834

[84] Cohen MS,Taunton J.A clickable inhibitor reveals context-dependent autoactivation of p90 RSK.Nat Chem Biol2007;3:156-60 PMCID:PMC3634365

[85] Bain J,Elliott M.The selectivity of protein kinase inhibitors: a further update.Biochem J2007;408:297-315 PMCID:PMC2267365

[86] Ludwik KA,Li M.Development of a RSK inhibitor as a novel therapy for triple-negative breast cancer.Mol Cancer Ther2016;15:2598-608 PMCID:PMC5807013

[87] Li M,Mrozowski RM.Synthesis and structure-activity relationship study of 5a-carbasugar analogues of SL0101.ACS Med Chem Lett2015;6:95-9 PMCID:PMC4291707

[88] Li M,Ludwik KA,Lannigan DA.Stereoselective synthesis and evaluation of C6″-substituted 5a-carbasugar analogues of SL0101 as inhibitors of RSK1/2.Org Lett2017;19:2410-3

[89] Li Y,Vemula R.Regioselective synthesis of a C-4'' carbamate,C-6'' n-Pr substituted cyclitol analogue of SL0101.Org Lett2020;22:1448-52 PMCID:PMC7292201

[90] Abdulrahman N,Joseph JM.Inhibition of p90 ribosomal S6 kinase potentiates cisplatin activity in A549 human lung adenocarcinoma cells.J Pharm Pharmacol2020;72:1536-45

[91] Zhang S,Lu ZY.Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines.Cell Oncol2022;45:1005-18

[92] Shi X,MacDonnell S,Yan C.The RSK inhibitor BIX02565 limits cardiac ischemia/reperfusion injury.J Cardiovasc Pharmacol Ther2016;21:177-86 PMCID:PMC4822162

[93] Chen W,Baade PD.Cancer statistics in China, 2015.CA Cancer J Clin2016;66:115-32

[94] Osseis M,Rassy N.Surgery for T4 colorectal cancer in older patients: determinants of outcomes.J Pers Med2022;12:1534 PMCID:PMC9504737

[95] Luchini C,Ligtenberg MJL.ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach.Ann Oncol2019;30:1232-43

[96] Adeleke S,Choy A.Microsatellite instability testing in colorectal patients with Lynch syndrome: lessons learned from a case report and how to avoid such pitfalls.Per Med2022;19:277-86

[97] Grothey A,Purdie DM.Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE).J Clin Oncol2008;26:5326-34

[98] Cunningham D,Siena S.Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.N Engl J Med2004;351:337-45

[99] Tol J,Cats A.Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer.N Engl J Med2009;360:563-72

[100] Song Y,Liu Y,Wei Y.Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer: current status in clinical trials.Genes Dis2023;10:76-88 PMCID:PMC10066287