Pivotal role of NF-κB in cellular senescence of experimental pituitary tumours

in Journal of Endocrinology

Correspondence should be addressed to A L De Paul: adepaul@cmefcm.uncor.edu
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The molecular mechanisms underlying the capability of pituitary tumours to avoid unregulated cell proliferation are still not well understood. However, the NF-κB transcription factor, which is able to modulate not only cellular senescence but also tumour progression, has emerged as a targeted candidate. This work was focused on the NF-κB role in cellular senescence during the progression of experimental pituitary tumours. Also, the contribution of the signalling pathways in senescence-associated NF-κB activation and the senescence-associated secretory phenotype (SASP) and pro-survival-NF-κB target genes transcription were analysed. A robust NF-κB activation was seen at E20–E40 of tumour development accompanied by a marked SA-β-Gal co-reactivity in the tumour pituitary parenchyma. The induction of TNFα and IL1-β as specific SASP-related NF-κB target genes as well as Bcl-2 and Bcl-xl pro-survival genes was shown to be accompanied by increases in the p-p38 MAPK protein levels, starting at the E20 stage and strengthening from 40 to 60 days of tumour growth. It is noteworthy that p-JNK displayed a similar pattern of activation during pituitary tumour development, while p-AKT and p-ERK1/2 were downregulated. By employing a pharmacological strategy to abrogate NF-κB activity, we demonstrated a marked reduction in SA-β-Gal activity and a slight decrease in Ki67 immunopositive cells after NF-κB blockade. These results suggest a central role for NF-κB in the regulation of the cellular senescence programme, leading to the strikingly benign intrinsic nature of pituitary adenomas.

 

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  • AcostaJCO’LoghlenABanitoAGuijarroMVAugertARaguzSFumagalliMDa CostaMBrownCPopovNet al. 2008 Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133 10061018. (https://doi.org/10.1016/j.cell.2008.03.038)

    • Search Google Scholar
    • Export Citation
  • AlexandrakiKIMunayem KhanMChahalHSDalantaevaNSTrivellinGBerneyDMCaronPPopovicVPfeiferMJordanSet al. 2012 Oncogene-induced senescence in pituitary adenomas and carcinomas. Hormones 11 297307. (https://doi.org/10.14310/horm.2002.1358)

    • Search Google Scholar
    • Export Citation
  • AsaSLEzzatS 2009 The pathogenesis of pituitary tumors. Annual Review of Pathology 4 97126. (https://doi.org/10.1146/annurev.pathol.4.110807.092259)

    • Search Google Scholar
    • Export Citation
  • BubiciCPapaSPhamCGZazzeroniFFranzosoG 2004 NF-kappaB and JNK: an intricate affair. Cell Cycle 3 15241529. (https://doi.org/10.4161/cc.3.12.1321)

    • Search Google Scholar
    • Export Citation
  • CampisiJRobertL 2014 Cell senescence: role in aging and age-related diseases. Interdisciplinary Topics in Gerontology 39 4561. (https://doi.org/10.1159/000358899)

    • Search Google Scholar
    • Export Citation
  • CarrenoGGonzalez-MeljemJMHastonSMartinez-BarberaJP 2017 Stem cells and their role in pituitary tumorigenesis. Molecular and Cellular Endocrinology 445 2734. (https://doi.org/10.1016/j.mce.2016.10.005)

    • Search Google Scholar
    • Export Citation
  • ChenZLiZChangYMaLXuWLiMLiJZhangWSunQAnXet al. 2015 Relationship between NF-kappaB, MMP-9, and MICA expression in pituitary adenomas reveals a new mechanism of pituitary adenomas immune escape. Neuroscience Letters 597 7783. (https://doi.org/10.1016/j.neulet.2015.04.025)

    • Search Google Scholar
    • Export Citation
  • ChesnokovaVZonisSRubinekTYuRBen-ShlomoAKovacsKWawrowskyKMelmedS 2007 Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth. Cancer Research 67 1056410572. (https://doi.org/10.1158/0008-5472.CAN-07-0974)

    • Search Google Scholar
    • Export Citation
  • ChesnokovaVZonisSKovacsKBen-ShlomoAWawrowskyKBannykhSMelmedS 2008 p21(Cip1) restrains pituitary tumor growth. PNAS 105 1749817503. (https://doi.org/10.1073/pnas.0804810105)

    • Search Google Scholar
    • Export Citation
  • ChesnokovaVZhouCAnatBSSvetlanaZYujiTSong-GuangRMelmedS 2013 Growth hormone is a cellular senescence target in pituitary and nonpituitary cells. PNAS 110 33313339. (https://doi.org/10.1073/pnas.1310589110)

    • Search Google Scholar
    • Export Citation
  • ChienYScuoppoCWangXFangXBalgleyBBoldenJEPremsrirutPLuoWChicasALeeCSet al. 2011 Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes and Development 25 21252136. (https://doi.org/10.1101/gad.17276711)

    • Search Google Scholar
    • Export Citation
  • CoppeJPPatilCKRodierFSunYMunozDPGoldsteinJNelsonPSDesprezPYCampisiJ 2008 Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology 6 28532868. (https://doi.org/10.1371/journal.pbio.0060301)

    • Search Google Scholar
    • Export Citation
  • CoppeJPDesprezPYKrtolicaACampisiJ 2010 The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathology 5 99118. (https://doi.org/10.1146/annurev-pathol-121808-102144)

    • Search Google Scholar
    • Export Citation
  • Courtois-CoxSGenther WilliamsSMReczekEEJohnsonBWMcGillicuddyLTJohannessenCMHollsteinPEMacCollinMCichowskiK 2006 A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10 459472. (https://doi.org/10.1016/j.ccr.2006.10.003)

    • Search Google Scholar
    • Export Citation
  • CuzzocreaSChatterjeePKMazzonEDugoLSerrainoIBrittiDMazzulloGCaputiAPThiemermannC 2002 Pyrrolidinedithiocarbamate attenuates the development of acute and chronic inflammation. British Journal of Pharmacology 135 496510. (https://doi.org/10.1038/sj.bjp.0704463)

    • Search Google Scholar
    • Export Citation
  • DonangeloIGutmanSHorvathEKovacsKWawrowskyKMountMMelmedS 2006 Pituitary tumor transforming gene overexpression facilitates pituitary tumor development. Endocrinology 147 47814791. (https://doi.org/10.1210/en.2006-0544)

    • Search Google Scholar
    • Export Citation
  • FranceschiCCampisiJ 2014 Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. Journals of Gerontology: Series A Biological Sciences and Medical Sciences 69 (Supplement 1) S4S9. (https://doi.org/10.1093/gerona/glu057)

    • Search Google Scholar
    • Export Citation
  • FreundAPatilCKCampisiJ 2011 P38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO Journal 30 15361548. (https://doi.org/10.1038/emboj.2011.69)

    • Search Google Scholar
    • Export Citation
  • Gonzalez-MeljemJMMartinez-BarberaJP 2018 Senescence drives non-cell autonomous tumorigenesis in the pituitary gland. Molecular and Cellular Oncology 5 e1435180. (https://doi.org/10.1080/23723556.2018.1435180)

    • Search Google Scholar
    • Export Citation
  • Gonzalez-MeljemJMHastonSCarrenoGAppsJRPozziSStacheCKaushalGVirasamiAPanousopoulosLMousavy-GharavySNet al. 2017 Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nature Communications 8 1819. (https://doi.org/10.1038/s41467-017-01992-5)

    • Search Google Scholar
    • Export Citation
  • HayesTKNeelNFHuCGautamPChenardMLongBAzizMKassnerMBryantKLPierobonMet al. 2016 Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression. Cancer Cell 29 7589. (https://doi.org/10.1016/j.ccell.2015.11.011)

    • Search Google Scholar
    • Export Citation
  • Hernandez-SeguraANehmeJDemariaM 2018 Hallmarks of cellular senescence. Trends in Cell Biology 28 436453. (https://doi.org/10.1016/j.tcb.2018.02.001)

    • Search Google Scholar
    • Export Citation
  • HuangWCJuTKHungMCChenCC 2007 Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Molecular Cell 26 7587. (https://doi.org/10.1016/j.molcel.2007.02.019)

    • Search Google Scholar
    • Export Citation
  • KarinM 2006 Nuclear factor-kappaB in cancer development and progression. Nature 441 431436. (https://doi.org/10.1038/nature04870)

  • KimYYJeeHJUmJHKimYMBaeSSYunJ 2017 Cooperation between p21 and Akt is required for p53-dependent cellular senescence. Aging Cell 16 10941103. (https://doi.org/10.1111/acel.12639)

    • Search Google Scholar
    • Export Citation
  • KuilmanTPeeperDS 2009 Senescence-messaging secretome: SMS-ing cellular stress. Nature Reviews: Cancer 9 8194. (https://doi.org/10.1038/nrc2560)

    • Search Google Scholar
    • Export Citation
  • KuilmanTMichaloglouCMooiWJPeeperDS 2010 The essence of senescence. Genes and Development 24 24632479. (https://doi.org/10.1101/gad.1971610)

    • Search Google Scholar
    • Export Citation
  • KwongJHongLLiaoRDengQHanJSunP 2009 p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms. Journal of Biological Chemistry 284 1123711246. (https://doi.org/10.1074/jbc.M808327200)

    • Search Google Scholar
    • Export Citation
  • LeeBYHanJAImJSMorroneAJohungKGoodwinECKleijerWJDiMaioDHwangES 2006 Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell 5 187195. (https://doi.org/10.1111/j.1474-9726.2006.00199.x)

    • Search Google Scholar
    • Export Citation
  • LiuSFYeXMalikAB 1999 Inhibition of NF-kappaB activation by pyrrolidinedithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation 100 13301337. (https://doi.org/10.1161/01.cir.100.12.1330)

    • Search Google Scholar
    • Export Citation
  • LiuKFengTLiuJZhongMZhangS 2012 Silencing of the DEK gene induces apoptosis and senescence in CaSki cervical carcinoma cells via the up-regulation of NF-kappaB p65. Bioscience Reports 32 323332. (https://doi.org/10.1042/BSR20100141)

    • Search Google Scholar
    • Export Citation
  • LloydRVScheithauerBWKurokiTVidalSKovacsKStefaneanuL 1999 Vascular endothelial growth factor (VEGF) expression in human pituitary adenomas and carcinomas. Endocrine Pathology 10 229235. (https://doi.org/10.1007/bf02738884)

    • Search Google Scholar
    • Export Citation
  • Lopez-OtinCBlascoMAPartridgeLSerranoMKroemerG 2013 The hallmarks of aging. Cell 153 11941217. (https://doi.org/10.1016/j.cell.2013.05.039)

    • Search Google Scholar
    • Export Citation
  • MaizaJCCaronP 2009 Pituitary carcinomas and aggressive adenomas: an overview and new therapeutic options. Annales d’Endocrinologie 70 (Supplement 1) S12S19. (https://doi.org/10.1016/S0003-4266(09)72471-0)

    • Search Google Scholar
    • Export Citation
  • MelmedS 2011 Pathogenesis of pituitary tumors. Nature Reviews: Endocrinology 7 257266. (https://doi.org/10.1038/nrendo.2011.40)

  • MelmedS 2015 Pituitary tumors. Endocrinology and Metabolism Clinics of North America 44 19. (https://doi.org/10.1016/j.ecl.2014.11.004)

    • Search Google Scholar
    • Export Citation
  • MertensFGremeauxLChenJFuQWillemsCRooseHGovaereORoskamsTCristinaCBecú-VillalobosDet al. 2015 Pituitary tumors contain a side population with tumor stem cell-associated characteristics. Endocrine-Related Cancer 22 481504. (https://doi.org/10.1530/ERC-14-0546)

    • Search Google Scholar
    • Export Citation
  • MiaoCLvYZhangWChaiXFengLFangYLiuXZhangX 2017 Pyrrolidinedithiocarbamate (PDTC) attenuates cancer cachexia by affecting muscle atrophy and fat lipolysis. Frontiers in Pharmacology 8 915. (https://doi.org/10.3389/fphar.2017.00915)

    • Search Google Scholar
    • Export Citation
  • MoiseevaODeschenes-SimardXSt-GermainEIgelmannSHuotGCadarAEBourdeauVPollakMNFerbeyreG 2013 Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 12 489498. (https://doi.org/10.1111/acel.12075)

    • Search Google Scholar
    • Export Citation
  • Mongi-BragatoBZamponiEGarcia-KellerCAssisMAVirgoliniMBMascoDHZimmerACancelaLM 2016 Enkephalin is essential for the molecular and behavioral expression of cocaine sensitization. Addiction Biology 21 326338. (https://doi.org/10.1111/adb.12200)

    • Search Google Scholar
    • Export Citation
  • MossBLElhammaliAFowlkesTGrossSVinjamooriAContagCHPiwnica-WormsD 2012 Interrogation of inhibitor of nuclear factor kappaB alpha/nuclear factor kappaB (IkappaBalpha/NF-kappaB) negative feedback loop dynamics: from single cells to live animals in vivo. Journal of Biological Chemistry 287 3135931370. (https://doi.org/10.1074/jbc.m112.364018)

    • Search Google Scholar
    • Export Citation
  • NogueiraLRuiz-OntanonPVazquez-BarqueroALafargaMBercianoMTAldazBGrandeLCasafontISeguraVRoblesEFet al. 2011 Blockade of the NFkappaB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo. Oncogene 30 35373548. (https://doi.org/10.1038/onc.2011.74)

    • Search Google Scholar
    • Export Citation
  • OrtizLDSyroLVScheithauerBWErsenAUribeHFadulCERotondoFHorvathEKovacsK 2012 Anti-VEGF therapy in pituitary carcinoma. Pituitary 15 445449. (https://doi.org/10.1007/s11102-011-0346-8)

    • Search Google Scholar
    • Export Citation
  • OzesONMayoLDGustinJAPfefferSRPfefferLMDonnerDB 1999 NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401 8285. (https://doi.org/10.1038/43466)

    • Search Google Scholar
    • Export Citation
  • PikarskyEPoratRMSteinIAbramovitchRAmitSKasemSGutkovich-PyestEUrieli-ShovalSGalunEBen-NeriahY 2004 NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431 461466. (https://doi.org/10.1038/nature02924)

    • Search Google Scholar
    • Export Citation
  • PlaceRFHaspeslaghDHubbardAKGiardinaC 2001 Cytokine-induced stabilization of newly synthesized I(kappa)B-alpha. Biochemical and Biophysical Research Communications 283 813820. (https://doi.org/10.1006/bbrc.2001.4883)

    • Search Google Scholar
    • Export Citation
  • PlaceRFHaspeslaghDGiardinaC 2003 Induced stabilization of IkappaBalpha can facilitate its re-synthesis and prevent sequential degradation. Journal of Cellular Physiology 195 470478. (https://doi.org/10.1002/jcp.10262)

    • Search Google Scholar
    • Export Citation
  • RovillainEMansfieldLCaetanoCAlvarez-FernandezMCaballeroOLMedemaRHHummerichHJatPS 2011 Activation of nuclear factor-kappa B signalling promotes cellular senescence. Oncogene 30 23562366. (https://doi.org/10.1038/onc.2010.611)

    • Search Google Scholar
    • Export Citation
  • SabatinoMEPetitiJPSosaL del VPerezPAGutierrezSLeimgruberCLatiniATorresAIDe PaulAL 2015 Evidence of cellular senescence during the development of estrogen-induced pituitary tumors. Endocrine-Related Cancer 22 299317. (https://doi.org/10.1530/ERC-14-0333)

    • Search Google Scholar
    • Export Citation
  • SabatinoMEGrondonaESosaLDVMongi BragatoBCarrenoLJuarezVda SilvaRARemorAde BortoliLde Paula MartinsRet al. 2018 Oxidative stress and mitochondrial adaptive shift during pituitary tumoral growth. Free Radical Biology and Medicine 120 4155. (https://doi.org/10.1016/j.freeradbiomed.2018.03.019)

    • Search Google Scholar
    • Export Citation
  • SalminenAKaarnirantaKHaapasaloAHiltunenMSoininenHAlafuzoffI 2012 Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Progress in Neurobiology 96 8795. (https://doi.org/10.1016/j.pneurobio.2011.11.005)

    • Search Google Scholar
    • Export Citation
  • SapochnikMFuertesMArztE 2017 Programmed cell senescence: role of IL-6 in the pituitary. Journal of Molecular Endocrinology 58 R241R253. (https://doi.org/10.1530/JME-17-0026)

    • Search Google Scholar
    • Export Citation
  • SatyanarayanaAGreenbergRASchaetzleinSBuerJMasutomiKHahnWCZimmermannSMartensUMannsMPRudolphKL 2004 Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Molecular and Cellular Biology 24 54595474. (https://doi.org/10.1128/MCB.24.12.5459-5474.2004)

    • Search Google Scholar
    • Export Citation
  • ScheithauerBWGaffeyTALloydRVSeboTJKovacsKTHorvathEYapicierOYoungWFJrMeyerFBKurokiTet al. 2006 Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59 341353; discussion 341353. (https://doi.org/10.1227/01.NEU.0000223437.51435.6E)

    • Search Google Scholar
    • Export Citation
  • SchramekDKotsinasAMeixnerAWadaTEllingUPospisilikJANeelyGGZwickRHSiglVForniGet al. 2011 The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression. Nature Genetics 43 212219. (https://doi.org/10.1038/ng.767)

    • Search Google Scholar
    • Export Citation
  • TammelaTSanchez-RiveraFJCetinbasNMWuKJoshiNSHeleniusKParkYAzimiRKerperNRWesselhoeftRAet al. 2017 A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature 545 355359. (https://doi.org/10.1038/nature22334)

    • Search Google Scholar
    • Export Citation
  • TilstraJSRobinsonARWangJGreggSQClausonCLReayDPNastoLASt CroixCMUsasAVoNet al. 2012 NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. Journal of Clinical Investigation 122 26012612. (https://doi.org/10.1172/JCI45785)

    • Search Google Scholar
    • Export Citation
  • TurnerHENagyZEsiriMMHarrisALWassJA 2000 Role of matrix metalloproteinase 9 in pituitary tumor behavior. Journal of Clinical Endocrinology and Metabolism 85 29312935. (https://doi.org/10.1210/jcem.85.8.6754)

    • Search Google Scholar
    • Export Citation
  • TyagiNBhardwajASinghAPMcClellanSCarterJESinghS 2014 p21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-kappaB pathway. Oncotarget 5 87788789. (https://doi.org/10.18632/oncotarget.2398)

    • Search Google Scholar
    • Export Citation
  • VenderJRLairdMDDhandapaniKM 2008 Inhibition of NFkappaB reduces cellular viability in GH3 pituitary adenoma cells. Neurosurgery 62 11221127; discussion 10271128. (https://doi.org/10.1227/01.neu.0000325874.82999.75)

    • Search Google Scholar
    • Export Citation
  • WangWChenJXLiaoRDengQZhouJJHuangSSunP 2002 Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Molecular and Cellular Biology 22 33893403. (https://doi.org/10.1128/mcb.22.10.3389-3403.2002)

    • Search Google Scholar
    • Export Citation
  • WernerSLBarkenDHoffmannA 2005 Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 309 18571861. (https://doi.org/10.1126/science.1113319)

    • Search Google Scholar
    • Export Citation
  • WernerSLKearnsJDZadorozhnayaVLynchCO’DeaEBoldinMPMaABaltimoreDHoffmannA 2008 Encoding NF-kappaB temporal control in response to TNF: distinct roles for the negative regulators IkappaBalpha and A20. Genes and Development 22 20932101. (https://doi.org/10.1101/gad.1680708)

    • Search Google Scholar
    • Export Citation
  • XiaYPadreRHurtado De MendozaTBotteroVTergaonkarVVermaI 2009 Phosphorylation of p53 by IκB kinase 2 promotes its degradation by β-TrCP PNAS 106 26292634. (https://doi.org/10.1073/pnas.0812256106)

    • Search Google Scholar
    • Export Citation
  • XiaYShenSVermaIM 2014 NF-kappaB, an active player in human cancers. Cancer Immunology Research 2 823830. (https://doi.org/10.1158/2326-6066.CIR-14-0112)

    • Search Google Scholar
    • Export Citation
  • XuWLiYYuanWWYinYSongWWWangYHuangQQZhaoWHWuJQ 2018 Membrane-bound CD40L promotes senescence and initiates senescence-associated secretory phenotype via NF-kappaB activation in lung adenocarcinoma. Cellular Physiology and Biochemistry 48 17931803. (https://doi.org/10.1159/000492352)

    • Search Google Scholar
    • Export Citation
  • YangHSunRMaNLiuQSunXZiPWangJChaoKYuL 2017 Inhibition of nuclear factor-kappaB signal by pyrrolidinedithiocarbamate alleviates lipopolysaccharide-induced acute lung injury. Oncotarget 8 4729647304. (https://doi.org/10.18632/oncotarget.17624)

    • Search Google Scholar
    • Export Citation