The proprotein convertase furin in cancer: more than an oncogene.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
31
08
2021
accepted:
30
12
2021
revised:
13
12
2021
pubmed:
9
1
2022
medline:
11
3
2022
entrez:
8
1
2022
Statut:
ppublish
Résumé
Furin is the first discovered proprotein convertase member and is present in almost all mammalian cells. Therefore, by regulating the maturation of a wide range of proproteins, Furin expression and/or activity is involved in various physiological and pathophysiological processes ranging from embryonic development to carcinogenesis. Since many of these protein precursors are involved in initiating and maintaining the hallmarks of cancer, Furin has been proposed as a potential target for treating several human cancers. In contrast, other studies have revealed that some types of cancer do not benefit from Furin inhibition. Therefore, understanding the heterogeneous functions of Furin in cancer will provide important insights into the design of effective strategies targeting Furin in cancer treatment. Here, we present recent advances in understanding how Furin expression and activity are regulated in cancer cells and their influences on the activity of Furin substrates in carcinogenesis. Furthermore, we discuss how Furin represses tumorigenic properties of several cancer cells and why Furin inhibition leads to aggressive phenotypes in other tumors. Finally, we summarize the clinical applications of Furin inhibition in treating human cancers.
Identifiants
pubmed: 34997216
doi: 10.1038/s41388-021-02175-9
pii: 10.1038/s41388-021-02175-9
doi:
Substances chimiques
FURIN protein, human
EC 3.4.21.75
Furin
EC 3.4.21.75
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1252-1262Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Puente XS, Sánchez LM, Overall CM, López-Otín C. Human and mouse proteases: a comparative genomic approach. Nat Rev Genet. 2003;4:544–58.
pubmed: 12838346
doi: 10.1038/nrg1111
Shakya M, Lindberg I. Mouse models of human proprotein convertase insufficiency. Endocr Rev. 2021;42:259–94.
pubmed: 33382413
doi: 10.1210/endrev/bnaa033
Roebroek AJM, Schalken JA, Bussemakers MJG, van Heerikhuizen H, Onnekink C, Debruyne FMJ, et al. Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene. Mol Biol Rep. 1986;11:117–25.
pubmed: 3488499
doi: 10.1007/BF00364823
Roebroek AJ, Schalken JA, Leunissen JA, Onnekink C, Bloemers HP, Van, et al. Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein. EMBO J. 1986;5:2197–202.
pubmed: 3023061
pmcid: 1167100
doi: 10.1002/j.1460-2075.1986.tb04484.x
Julius D, Brake A, Blair L, Kunisawa R, Thorner J. Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-alpha-factor. Cell. 1984;37:1075–89.
pubmed: 6430565
doi: 10.1016/0092-8674(84)90442-2
Van de Ven WJ, Creemers JW, Roebroek AJ. Furin: the prototype mammalian subtilisin-like proprotein-processing enzyme. Endoproteolytic cleavage at paired basic residues of proproteins of the eukaryotic secretory pathway. Enzyme. 1991;45:257–70.
pubmed: 1843280
doi: 10.1159/000468900
Coppola I, Brouwers B, Meulemans S, Ramos-Molina B, Creemers JWM. Differential effects of furin deficiency on insulin receptor processing and glucose control in liver and pancreatic β cells of mice. Int J Mol Sci. 2021;22:6344.
pubmed: 34198511
pmcid: 8231939
doi: 10.3390/ijms22126344
Roebroek AJM, Taylor NA, Louagie E, Pauli I, Smeijers L, Snellinx A, et al. Limited redundancy of the proprotein convertase furin in mouse liver. J Biol Chem. 2004;279:53442–50.
pubmed: 15471862
doi: 10.1074/jbc.M407152200
Kara I, Poggi M, Bonardo B, Govers R, Landrier JF, Tian S, et al. The paired basic amino acid-cleaving enzyme 4 (PACE4) is involved in the maturation of insulin receptor isoform B: An opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2). J Biol Chem. 2015;290:2812–21.
pubmed: 25527501
doi: 10.1074/jbc.M114.592543
He Z, Thorrez L, Siegfried G, Meulemans S, Evrard S, Tejpar S, et al. The proprotein convertase furin is a pro-oncogenic driver in KRAS and BRAF driven colorectal cancer. Oncogene. 2020;39:3571–87.
pubmed: 32139876
doi: 10.1038/s41388-020-1238-z
Tomé M, Pappalardo A, Soulet F, López JJ, Olaizola J, Leger Y, et al. Inactivation of proprotein convertases in T cells Inhibits PD-1 expression and creates a favorable immune microenvironment in colorectal cancer. Cancer Res. 2019;79:5008–21.
pubmed: 31358531
doi: 10.1158/0008-5472.CAN-19-0086
Khatib AM, Siegfried G, Prat A, Luis J, Chrétien M, Metrakos P, et al. Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells: Importance of insulin-like growth factor-1 (IGF-1) receptor processing in IGF-1-mediated functions. J Biol Chem. 2001;276:30686–93.
pubmed: 11402025
doi: 10.1074/jbc.M101725200
Scamuffa N, Siegfried G, Bontemps Y, Ma L, Basak A, Cherel G, et al. Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells. J Clin Invest. 2008;118:352–63.
pubmed: 18064302
doi: 10.1172/JCI32040
Oh J, Barve M, Matthews CM, Koon EC, Heffernan TP, Fine B, et al. Phase II study of Vigil® DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer. Gynecol Oncol. 2016;143:504–10.
pubmed: 27678295
doi: 10.1016/j.ygyno.2016.09.018
Rocconi RP, Stevens EE, Bottsford-Miller JN, Ghamande SA, Aaron P, Wallraven G, et al. A phase I combination study of vigil and atezolizumab in recurrent/refractory advanced-stage ovarian cancer: Efficacy assessment in BRCA1/2-wt patients. J Clin Oncol. 2020;38:3002.
doi: 10.1200/JCO.2020.38.15_suppl.3002
Huang YH, Lin KH, Liao CH, Lai MW, Tseng YH, Yeh CT. Furin overexpression suppresses tumor growth and predicts a better postoperative disease-free survival in hepatocellular carcinoma. PLoS One. 2012;7:1–10.
Declercq J, Brouwers B, Pruniau VPEG, Stijnen P, Tuand K, Meulemans S, et al. Liver-specific inactivation of the proprotein convertase FURIN leads to increased hepatocellular carcinoma growth. Biomed Res Int. 2015;2015:148651.
pubmed: 26167473
pmcid: 4475760
doi: 10.1155/2015/148651
Declercq J, Ramos-Molina B, Sannerud R, Brouwers B, Pruniau VPEG, Meulemans S. et al. Endosome to trans-Golgi network transport of proprotein convertase 7 is mediated by a cluster of basic amino acids and palmitoylated cysteines. Eur J Cell Biol. 2017;96:432–9.
pubmed: 28413120
doi: 10.1016/j.ejcb.2017.03.010
Griffiths G, Simons K. The trans Golgi network: sorting at the exit site of the Golgi complex. Science. 1986;234:438–43.
pubmed: 2945253
doi: 10.1126/science.2945253
Molloy SS, Anderson ED, Jean F, Thomas G. Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends Cell Biol. 1999;9:28–35.
pubmed: 10087614
doi: 10.1016/S0962-8924(98)01382-8
Plaimauer B, Mohr G, Wernhart W, Himmelspach M, Dorner F, Schlokat U. ‘Shed’ furin: mapping of the cleavage determinants and identification of its C-terminus. Biochem J. 2001;354:689.
pubmed: 11237874
pmcid: 1221701
doi: 10.1042/bj3540689
Mesnard D, Donnison M, Fuerer C, Pfeffer PL, Constam DB. The microenvironment patterns the pluripotent mouse epiblast through paracrine furin and Pace4 proteolytic activities. Genes Dev. 2011;25:1871–80.
pubmed: 21896659
pmcid: 3175722
doi: 10.1101/gad.16738711
Paleyanda RK, Drews R, Lee TK, Luboń H. Secretion of human furin into mouse milk. J Biol Chem. 1997;272:15270–4.
pubmed: 9182552
doi: 10.1074/jbc.272.24.15270
Ginefra P, Filippi BGH, Donovan P, Bessonnard S, Constam DB. Compartment-specific biosensors reveal a complementary subcellular distribution of bioactive Furin and PC7. Cell Rep. 2018;22:2176–89.
pubmed: 29466742
doi: 10.1016/j.celrep.2018.02.005
Susan-Resiga D, Essalmani R, Hamelin J, Asselin MC, Benjannet S, Chamberland A, et al. Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10. J Biol Chem. 2011;286:22785–94.
pubmed: 21550985
pmcid: 3123046
doi: 10.1074/jbc.M111.233577
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419.
pubmed: 25613900
doi: 10.1126/science.1260419
Uhlen M, Karlsson MJ, Zhong W, Tebani A, Pou C, Mikes J, et al. A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science. 2019;366:eaax9198.
Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, et al. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature. 2008;455:246–50.
pubmed: 18701887
pmcid: 2758057
doi: 10.1038/nature07210
van der Veeken J, Gonzalez AJ, Cho H, Arvey A, Hemmers S, Leslie CS, et al. Memory of inflammation in regulatory T cells. Cell. 2016;166:977–90.
pubmed: 27499023
pmcid: 4996371
doi: 10.1016/j.cell.2016.07.006
Creemers JWM, Khatib A-M. Knock-out mouse models of proprotein convertases: unique functions or redundancy? Front Biosci. 2008;13:4960–71.
pubmed: 18508561
doi: 10.2741/3055
Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science. 2001;294:1945–8.
pubmed: 11729324
doi: 10.1126/science.1065057
Cao J, Rehemtulla A, Pavlaki M, Kozarekar P, Chiarelli C. Furin directly cleaves proMMP-2 in the trans-golgi network resulting in a nonfunctioning proteinase. J Biol Chem. 2005;280:10974–80.
pubmed: 15637056
doi: 10.1074/jbc.M412370200
Soulet F, Bodineau C, Hooks KB, Descarpentrie J, Alves I, Dubreuil M, et al. ELA/APELA precursor cleaved by furin displays tumor suppressor function in renal cell carcinoma through mTORC1 activation. JCI Insight. 2020;5:e129070.
pmcid: 7453911
doi: 10.1172/jci.insight.129070
Tian S, Huang Q, Fang Y, Wu J. FurinDB: a database of 20-residue furin cleavage site motifs, substrates and their associated drugs. Int J Mol Sci. 2011;12:1060–5.
pubmed: 21541042
pmcid: 3083689
doi: 10.3390/ijms12021060
Shiryaev SA, Chernov AV, Golubkov VS, Thomsen ER, Chudin E, Chee MS, et al. High-resolution analysis and functional mapping of cleavage sites and substrate proteins of furin in the human proteome. PLoS One. 2013;8:1–12.
doi: 10.1371/journal.pone.0054290
Siegfried G, Basak A, Prichett-Pejic W, Scamuffa N, Ma L, Benjannet S, et al. Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases. Oncogene. 2005;24:6925–35.
pubmed: 16007151
doi: 10.1038/sj.onc.1208838
Scamuffa N, Sfaxi F, Ma J, Lalou C, Seidah N, Calvo F, et al. Prodomain of the proprotein convertase subtilisin/kexin Furin (ppFurin) protects from tumor progression and metastasis. Carcinogenesis. 2014;35:528–36.
pubmed: 24127186
doi: 10.1093/carcin/bgt345
He Z, Khatib A-M, Creemers JWM. Loss of proprotein convertase furin in mammary gland impairs proIGF1R and proIR processing and suppresses tumorigenesis in triple negative breast cancer. Cancers (Basel). 2020;12:2686.
doi: 10.3390/cancers12092686
He Z, Khatib A, Creemers JWM. Loss of the proprotein convertase Furin in T cells represses mammary tumorigenesis in oncogene-driven triple negative breast cancer. Cancer Lett. 2020;484:40–9.
pubmed: 32389711
doi: 10.1016/j.canlet.2020.05.001
Lapierre M, Siegfried G, Scamuffa N, Bontemps Y, Calvo F, Seidah NG, et al. Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells’ malignant phenotypes: Role of tissue inhibitors of metalloproteinase-1. Cancer Res. 2007;67:9030–4.
pubmed: 17909005
doi: 10.1158/0008-5472.CAN-07-0807
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
doi: 10.1016/j.cell.2011.02.013
Duguay SJ, Milewski WM, Young BD, Nakayama K, Steiner DF. Processing of wild-type and mutant proinsulin-like growth factor-IA by subtilisin-related proprotein convertases. J Biol Chem. 1997;272:6663–70.
pubmed: 9045697
doi: 10.1074/jbc.272.10.6663
Duguay SJ, Jin Y, Stein J, Duguay AN, Gardner P, Steiner DF. Post-translational processing of the insulin-like growth factor-2 precursor. Analysis of O-glycosylation and endoproteolysis. J Biol Chem. 1998;273:18443–51.
pubmed: 9660813
doi: 10.1074/jbc.273.29.18443
Liefers-Visser JAL, Meijering RAM, Reyners AKL, van der Zee AGJ, de Jong S. IGF system targeted therapy: Therapeutic opportunities for ovarian cancer. Cancer Treat Rev. 2017;60:90–9.
pubmed: 28934637
doi: 10.1016/j.ctrv.2017.08.012
Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018;17:1–14.
pubmed: 29304823
pmcid: 5755155
doi: 10.1186/s12943-017-0753-1
Zhang Y, Zhou M, Wei H, Zhou H, He J, Lu Y, et al. Furin promotes epithelial-mesenchymal transition in pancreatic cancer cells via Hippo-YAP pathway. Int J Oncol. 2017;50:1352–62.
pubmed: 28259973
doi: 10.3892/ijo.2017.3896
Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:0057–61.
Ramirez C, Hauser AD, Vucic EA, Bar-Sagi D. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis. Nature. 2019;576:477–81.
pubmed: 31827278
pmcid: 7048194
doi: 10.1038/s41586-019-1831-x
Louagie E, Taylor NA, Flamez D, Roebroek AJM, Bright NA, Meulemans S, et al. Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate. Proc Natl Acad Sci USA. 2008;105:12319–24.
pubmed: 18713856
pmcid: 2527909
doi: 10.1073/pnas.0800340105
Hasegawa-Minato J, Toyoshima M, Ishibashi M, Zhang X, Shigeta S, Grandori C, et al. Novel cooperative pathway of c-Myc and Furin, a pro-protein convertase, in cell proliferation as a therapeutic target in ovarian cancers. Oncotarget. 2018;9:3483–96.
pubmed: 29423060
doi: 10.18632/oncotarget.23322
De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17:457–74.
pubmed: 28706266
doi: 10.1038/nrc.2017.51
Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 1997;16:3898–911.
pubmed: 9233800
pmcid: 1170014
doi: 10.1093/emboj/16.13.3898
McColl BK, Paavonen K, Karnezis T, Harris NC, Davydova N, Rothacker J, et al. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J. 2007;21:1088–98.
pubmed: 17242158
doi: 10.1096/fj.06-7060com
Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chrétien M, et al. The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest. 2003;111:1723–32.
pubmed: 12782675
pmcid: 156106
doi: 10.1172/JCI200317220
Ma J, Evrard S, Badiola I, Siegfried G, Khatib A-M. Regulation of the proprotein convertases expression and activity during regenerative angiogenesis: Role of hypoxia-inducible factor (HIF). Eur J Cell Biol. 2017;96:457–68.
pubmed: 28624236
doi: 10.1016/j.ejcb.2017.06.001
Khatib AM, Lahlil R, Hagedorn M, Delomenie C, Christophe O, Denis C, et al. Biological outcome and mapping of total factor cascades in response to HIF induction during regenerative angiogenesis. Oncotarget. 2016;7:12102–20.
pubmed: 26933814
pmcid: 4914272
doi: 10.18632/oncotarget.7728
Siegfried G, Khatib A-MM, Benjannet S, Chrétien M, Seidah NG. The proteolytic processing of pro-platelet-derived growth factor-a at RRKR86 by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity. Cancer Res. 2003;63:1458–63.
pubmed: 12670890
Jaaks P, D’Alessandro V, Grob N, Büel S, Hajdin K, Schäfer BW, et al. The proprotein convertase furin contributes to rhabdomyosarcoma malignancy by promoting vascularization, migration and invasion. PLoS One. 2016;11:e0161396.
pubmed: 27548722
pmcid: 4993484
doi: 10.1371/journal.pone.0161396
Adams RH, Lohrum M, Klostermann A, Betz H, Püschel AW. The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. EMBO J. 1997;16:6077–86.
pubmed: 9321387
pmcid: 1326291
doi: 10.1093/emboj/16.20.6077
Mumblat Y, Kessler O, Ilan N, Neufeld G. Full-length semaphorin-3C is an inhibitor of tumor lymphangiogenesis and metastasis. Cancer Res. 2015;75:2177–86.
pubmed: 25808871
doi: 10.1158/0008-5472.CAN-14-2464
Doçi CL, Mikelis CM, Lionakis MS, Molinolo AA, Gutkind JS. Genetic identification of SEMA3F as an antilymphangiogenic metastasis suppressor gene in head and neck squamous carcinoma. Cancer Res. 2015;75:2937–48.
pubmed: 25952650
pmcid: 4538958
doi: 10.1158/0008-5472.CAN-14-3121
Parker MW, Hellman LM, Xu P, Fried MG, Vander Kooi CW. Furin processing of semaphorin 3F determines its anti-angiogenic activity by regulating direct binding and competition for neuropilin. Biochemistry. 2010;49:4068–75.
pubmed: 20387901
doi: 10.1021/bi100327r
Varshavsky A, Kessler O, Abramovitch S, Kigel B, Zaffryar S, Akiri G, et al. Semaphorin-3B is an angiogenesis inhibitor that is inactivated by furin-like pro-protein convertases. Cancer Res. 2008;68:6922–31.
pubmed: 18757406
doi: 10.1158/0008-5472.CAN-07-5408
Christensen C, Ambartsumian N, Gilestro G, Thomsen B, Comoglio P, Tamagnone L, et al. Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 2005;65:6167–77.
pubmed: 16024618
doi: 10.1158/0008-5472.CAN-04-4309
Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E, et al. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med. 2012;4:234–50.
pubmed: 22247010
pmcid: 3376853
doi: 10.1002/emmm.201100205
Sugano Y, Matsuzaki K, Tahashi Y, Furukawa F, Mori S, Yamagata H, et al. Distortion of autocrine transforming growth factor β signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells. Oncogene. 2003;22:2309–21.
pubmed: 12700666
doi: 10.1038/sj.onc.1206305
McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM. Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem. 2006;281:24171–81.
pubmed: 16815840
doi: 10.1074/jbc.M604507200
Fu J, Zhang J, Gong Y, Testa CL, Klein-Szanto AJ. Regulation of HIF-1 alpha by the proprotein convertases furin and PC7 in human squamous carcinoma cells. Mol Carcinog. 2015;54:698–706.
pubmed: 24436242
doi: 10.1002/mc.22131
Bommireddy R, Doetschman T. TGFβ1 and Treg cells: alliance for tolerance. Trends Mol Med. 2007;13:492–501.
pubmed: 17977791
pmcid: 2805009
doi: 10.1016/j.molmed.2007.08.005
Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2021;18:9–34.
pubmed: 32710082
doi: 10.1038/s41571-020-0403-1
Chen W, Ten Dijke P. Immunoregulation by members of the TGFβ superfamily. Nat Rev Immunol. 2016;16:723–40.
pubmed: 27885276
doi: 10.1038/nri.2016.112
Ghisoli M, Barve M, Schneider R, Mennel R, Lenarsky C, Wallraven G, et al. Pilot trial of FANG immunotherapy in ewing’s sarcoma. Mol Ther. 2015;23:1103–9.
pubmed: 25917459
pmcid: 4817748
doi: 10.1038/mt.2015.43
Nemunaitis J, Barve M, Orr D, Kuhn J, Magee M, Lamont J, et al. Summary of bi-shRNA furin /GM-CSF augmented autologous tumor cell immunotherapy (FANGTM) in advanced cancer of the liver. Oncol. 2014;87:21–9.
doi: 10.1159/000360993
Blanchette F, Rudd P, Grondin F, Attisano L, Dubois CM. Involvement of Smads in TGFbeta1-induced furin (fur) transcription. J Cell Physiol. 2001;188:264–73.
pubmed: 11424093
doi: 10.1002/jcp.1116
Bilbao D, Luciani L, Johannesson B, Piszczek A, Rosenthal N. Insulin‐like growth factor‐1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol Med. 2014;6:1423–35.
pubmed: 25339185
pmcid: 4237469
doi: 10.15252/emmm.201303376
Kusmartsev S, Gabrilovich DI. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother. 2006;55:237–45.
pubmed: 16047143
doi: 10.1007/s00262-005-0048-z
Cordova ZM, Grönholm A, Kytölä V, Taverniti V, Hämäläinen S, Aittomäki S, et al. Myeloid cell expressed proprotein convertase FURIN attenuates inflammation. Oncotarget. 2016;7:54392–404.
pubmed: 27527873
pmcid: 5342350
doi: 10.18632/oncotarget.11106
Rose M, Duhamel M, Rodet F, Salzet M. The role of proprotein convertases in the regulation of the function of immune cells in the oncoimmune response. Front Immunol. 2021;12:1–10.
doi: 10.3389/fimmu.2021.667850
DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019;19:369–82.
pubmed: 30718830
pmcid: 7339861
doi: 10.1038/s41577-019-0127-6
Vähätupa M, Aittomäki S, Martinez Cordova Z, May U, Prince S, Uusitalo-Järvinen H, et al. T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development. Oncoimmunology. 2016;5:1–11.
doi: 10.1080/2162402X.2016.1245266
Lissitzky JC, Luis J, Munzer JS, Benjannet S, Parat F, Chrétien M, et al. Endoproteolytic processing of integrin pro-α subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7. Biochem J. 2000;346:133–8.
pubmed: 10657249
pmcid: 1220832
doi: 10.1042/bj3460133
Bergeron E, Basak A, Decroly E, Seidah NG. Processing of α4 integrin by the proprotein convertases: Histidine at position P6 regulates cleavage. Biochem J. 2003;373:475–84.
pubmed: 12691605
pmcid: 1223497
doi: 10.1042/bj20021630
Lehmann M, Rigot V, Seidah NG, Marvaldi J, Lissitzky JC. Lack of integrin α-chain endoproteolytic cleavage in furin-deficient human colon adenocarcinoma cells LoVo. Biochem J. 1996;317:803–9.
pubmed: 8760366
pmcid: 1217556
doi: 10.1042/bj3170803
Felding-Habermann B, O’Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, et al. Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA. 2001;98:1853–8.
pubmed: 11172040
pmcid: 29346
doi: 10.1073/pnas.98.4.1853
Sawada K, Mitra AK, Radjabi AR, Bhaskar V, Kistner EO, Tretiakova M, et al. Loss of E-cadherin promotes ovarian cancer metastasis via α5-integrin, which is a therapeutic target. Cancer Res. 2008;68:2329–39.
pubmed: 18381440
pmcid: 2665934
doi: 10.1158/0008-5472.CAN-07-5167
Posthaus H, Dubois CM, Laprise MH, Grondin F, Suter MM, Müller E. Proprotein cleavage of E-cadherin by furin in baculovirus over-expression system: Potential role of other convertases in mammalian cells. FEBS Lett. 1998;438:306–10.
pubmed: 9827567
doi: 10.1016/S0014-5793(98)01330-1
Maret D, Gruzglin E, Sadr MS, Siu V, Shan W, Koch AW, et al. Surface expression of precursor N-cadherin promotes tumor cell invasion. Neoplasia. 2010;12:1066–80.
pubmed: 21170270
pmcid: 3003141
doi: 10.1593/neo.10954
Yu W, Yang L, Li T, Zhang Y. Cadherin signaling in cancer: its functions and role as a therapeutic target. Front Oncol. 2019;9:989.
pubmed: 31637214
pmcid: 6788064
doi: 10.3389/fonc.2019.00989
Duval S, Abu-Thuraia A, Elkholi IE, Chen R, Seebun D, Mayne J, et al. Shedding of cancer susceptibility candidate 4 by the convertases PC7/furin unravels a novel secretory protein implicated in cancer progression. Cell Death Dis. 2020;11:665.
pubmed: 32820145
pmcid: 7441151
doi: 10.1038/s41419-020-02893-0
Khatib AM, Kontogiannea M, Fallavollita L, Jamison B, Meterissian S, Brodt P. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res. 1999;59:1356–61.
pubmed: 10096570
Khatib AM, Auguste P, Fallavollita L, Wang N, Samani A, Kontogiannea M, et al. Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am J Pathol. 2005;167:749–59.
pubmed: 16127154
pmcid: 1698732
doi: 10.1016/S0002-9440(10)62048-2
Takino T, Sato H, Shinagawa A, Seiki M. Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library: MT-MMPs form a unique membrane-type subclass in the MMP family. J Biol Chem. 1995;270:23013–20.
pubmed: 7559440
doi: 10.1074/jbc.270.39.23013
Pei D. Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP. J Biol Chem. 1999;274:8925–32.
pubmed: 10085137
doi: 10.1074/jbc.274.13.8925
Ueda J, Kajita M, Suenaga N, Fujii K, Seiki M. Sequence-specific silencing of MT1-MMP expression suppresses tumor cell migration and invasion: importance of MT1-MMP as a therapeutic target for invasive tumors. Oncogene. 2003;22:8716–22.
pubmed: 14647466
doi: 10.1038/sj.onc.1206962
Khatib AM, Siegfried G, Chrétien M, Metrakos P, Seidah NG. Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. Am J Pathol. 2002;160:1921–35.
pubmed: 12057895
pmcid: 1850825
doi: 10.1016/S0002-9440(10)61140-6
Bassi DE, Mahloogi H, Al-Saleem L, De Cicco RL, Ridge JA, Klein-Szanto AJP. Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. Mol Carcinog. 2001;31:224–32.
pubmed: 11536372
doi: 10.1002/mc.1057
Bassi DE, De Cicco RL, Mahloogi H, Zucker S, Thomas G, Klein-Szanto AJP. Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells. Proc Natl Acad Sci USA. 2001;98:10326–31.
pubmed: 11517338
pmcid: 56960
doi: 10.1073/pnas.191199198
Loechel F, Gilpin BJ, Engvall E, Albrechtsen R, Wewer UM. Human ADAM 12 (Meltrin α) is an active metalloprotease. J Biol Chem. 1998;273:16993–7.
pubmed: 9642263
doi: 10.1074/jbc.273.27.16993
Schlöndorff J, Becherer JD, Blobel CP. Intracellular maturation and localization of the tumour necrosis factor α convertase (TACE). Biochem J. 2000;347:131–8.
pubmed: 10727411
pmcid: 1220940
doi: 10.1042/bj3470131
Siegfried G, Descarpentrie J, Evrard S, Khatib AM. Proprotein convertases: Key players in inflammation-related malignancies and metastasis. Cancer Lett. 2020;473:50–61.
pubmed: 31899298
doi: 10.1016/j.canlet.2019.12.027
Mbikay M, Sirois F, Yao J, Seidah NG, Chrétien M. Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. Br J Cancer. 1997;75:1509–14.
pubmed: 9166946
pmcid: 2223512
doi: 10.1038/bjc.1997.258
Cheng M, Watson PH, Paterson JA, Seidah N, Chrétien M, Shiu RPC. Pro-protein convertase gene expression in human breast cancer. Int J Cancer. 1997;71:966–71.
pubmed: 9185698
doi: 10.1002/(SICI)1097-0215(19970611)71:6<966::AID-IJC10>3.0.CO;2-4
Huo X, Zhou X, Peng P, Yu M, Zhang Y, Yang J, et al. Identification of a six-gene signature for predicting the overall survival of cervical cancer patients. Onco Targets Ther. 2021;14:809–22.
pubmed: 33574675
pmcid: 7873033
doi: 10.2147/OTT.S276553
Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–W560.
pubmed: 31114875
pmcid: 6602440
doi: 10.1093/nar/gkz430
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer Genomics Portal: An open platform for exploring multidimensional cancer genomics data. Cancer Disco. 2012;2:401–4.
doi: 10.1158/2159-8290.CD-12-0095
Ghisoli M, Barve M, Mennel R, Lenarsky C, Horvath S, Wallraven G, et al. Three-year follow up of GMCSF/bi-shRNA(furin) DNA-transfected autologous tumor immunotherapy (Vigil) in metastatic advanced Ewing’s sarcoma. Mol Ther. 2016;24:1478–83.
pubmed: 27109631
pmcid: 5023386
doi: 10.1038/mt.2016.86
Lei RX, Shi H, Peng XM, Zhu YH, Cheng J, Chen GH. Influence of a single nucleotide polymorphism in the P1 promoter of the furin gene on transcription activity and hepatitis B virus infection. Hepatology. 2009;50:763–71.
pubmed: 19492430
doi: 10.1002/hep.23062
Turpeinen H, Raitoharju E, Oksanen A, Oksala N, Levula M, Lyytikäinen L-P, et al. Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL. Atherosclerosis. 2011;219:799–806.
pubmed: 21889147
doi: 10.1016/j.atherosclerosis.2011.08.011
Declercq J, Jacobs B, Biesmans B, Roth A, Klingbiel D, Tejpar S, et al. Single nucleotide polymorphism (rs4932178) in the P1 promoter of FURIN is not prognostic to colon cancer. Biomed Res Int. 2015;2015:321276.
Sarkar FH, Adsule S, Li Y, Padhye S. Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem. 2007;7:599–608.
pubmed: 17584158
doi: 10.2174/138955707780859431
Neel J-C, Humbert L, Lebrun J-J. The dual role of TGFβ in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol. 2012;2012:1–28.
doi: 10.5402/2012/381428
Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S, Kurth E, et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene. 2016;35:6077–86.
pubmed: 27157619
pmcid: 5102827
doi: 10.1038/onc.2016.133
Lowell S, Jones P, Le Roux I, Dunne J, Watt FM. Stimulation of human epidermal differentiation by Delta-Notch signalling at the boundaries of stem-cell clusters. Curr Biol. 2000;10:491–500.
pubmed: 10801437
doi: 10.1016/S0960-9822(00)00451-6
Westhoff B, Colaluca IN, D’Ario G, Donzelli M, Tosoni D, Volorio S, et al. Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci USA. 2009;106:22293–8.
pubmed: 20007775
pmcid: 2799768
doi: 10.1073/pnas.0907781106
Baumgart A, Mazur PK, Anton M, Rudelius M, Schwamborn K, Feuchtinger A, et al. Opposing role of Notch1 and Notch2 in a Kras G12D -driven murine non-small cell lung cancer model. Oncogene. 2015;34:578–88.
pubmed: 24509876
doi: 10.1038/onc.2013.592
Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-∅ from cells. Nature. 1997;385:729–33.
pubmed: 9034190
doi: 10.1038/385729a0
Srour N, Lebel A, McMahon S, Fournier I, Fugère M, Day R, et al. TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity. FEBS Lett. 2003;554:275–83.
pubmed: 14623079
doi: 10.1016/S0014-5793(03)01159-1
Chang LY, Lin YC, Chiang JM, Mahalingam J, Su SH, Huang CT, et al. Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion. Oncoimmunology. 2015;4:e1040215.
Zhao XX, Rong L, Zhao XX, Li X, Liu X, Deng J, et al. TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest. 2012;122:4094–104.
pubmed: 23064360
pmcid: 3484453
doi: 10.1172/JCI64115
Bertrand F, Rochotte J, Colacios C, Montfort A, Tilkin-Mariamé AF, Touriol C, et al. Blocking tumor necrosis factor α enhances CD8 T-cell-dependent immunity in experimental melanoma. Cancer Res. 2015;75:2619–28.
pubmed: 25977337
doi: 10.1158/0008-5472.CAN-14-2524
Hartley G, Regan D, Guth A, Dow S. Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α. Cancer Immunol Immunother. 2017;66:523–35.
pubmed: 28184968
pmcid: 6469500
doi: 10.1007/s00262-017-1955-5
Kearney CJ, Vervoort SJ, Hogg SJ, Ramsbottom KM, Freeman AJ, Lalaoui N, et al. Tumor immune evasion arises through loss of TNF sensitivity. Sci Immunol. 2018;3:1–15.
doi: 10.1126/sciimmunol.aar3451
Garancher A, Suzuki H, Haricharan S, Chau LQ, Masihi MB, Rusert JM, et al. Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma. Nat Neurosci. 2020;23:842–53.
pubmed: 32424282
pmcid: 7456619
doi: 10.1038/s41593-020-0628-4
Sarac MS, Cameron A, Lindberg I. The furin inhibitor hexa-D-arginine blocks the activation of Pseudomonas aeruginosa exotoxin a in vivo. Infect Immun. 2002;70:7136–9.
pubmed: 12438396
pmcid: 133042
doi: 10.1128/IAI.70.12.7136-7139.2002
Yakala GK, Cabrera-Fuentes HA, Crespo-Avilan GE, Rattanasopa C, Burlacu A, George BL, et al. FURIN inhibition reduces vascular remodeling and atherosclerotic lesion progression in mice. Arterioscler Thromb Vasc Biol. 2019;39:387–401.
pubmed: 30651003
pmcid: 6393193
doi: 10.1161/ATVBAHA.118.311903
Senzer N, Barve M, Kuhn J, Melnyk A, Beitsch P, Lazar M, et al. Phase i trial of bi-shRNAi furin/GMCSF DNA/autologous tumor cell vaccine (FANG) in advanced cancer. Mol Ther. 2012;20:679–86.
pubmed: 22186789
doi: 10.1038/mt.2011.269
Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554:538–43.
pubmed: 29443964
doi: 10.1038/nature25492
Oh J, Barve M, Matthews CM, Koon EC, Heffernan TP, Fine B, et al. Phase II study of Vigil® DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer. Gynecol Oncol. 2016;143:504–10.
pubmed: 27678295
doi: 10.1016/j.ygyno.2016.09.018
Ghisoli M, Rutledge M, Stephens PJ, Mennel R, Barve M, Manley M, et al. Case report: immune-mediated complete response in a patient with recurrent advanced ewing sarcoma (EWS) After Vigil Immunotherapy. J Pediatr Hematol Oncol. 2017;39:e183–e186.
pubmed: 28338569
doi: 10.1097/MPH.0000000000000822
Zhu J, Declercq J, Roucourt B, Ghassabeh GH, Meulemans S, Kinne J, et al. Generation and characterization of non-competitive furin-inhibiting nanobodies. Biochem J. 2012;448:73–82.
pubmed: 22920187
doi: 10.1042/BJ20120537
Couture F, Kwiatkowska A, Dory YL, Day R. Therapeutic uses of furin and its inhibitors: a patent review. Expert Opin Ther Pat. 2015;25:379–96.
pubmed: 25563687
doi: 10.1517/13543776.2014.1000303
Klein-Szanto AJ, Bassi DE. Proprotein convertase inhibition: paralyzing the cell’s master switches. Biochem Pharm. 2017;140:8–15.
pubmed: 28456517
doi: 10.1016/j.bcp.2017.04.027
Levesque C, Fugère M, Kwiatkowska A, Couture F, Desjardins R, Routhier S, et al. The multi-leu peptide inhibitor discriminates between pace4 and furin and exhibits antiproliferative effects on prostate cancer cells. J Med Chem. 2012;55:10501–11.
pubmed: 23126600
pmcid: 3523546
doi: 10.1021/jm3011178
Bassi DE, Zhang J, Renner C, Klein-Szanto AJ. Targeting proprotein convertases in furin-rich lung cancer cells results in decreased in vitro and in vivo growth. Mol Carcinog. 2017;56:1182–8.
pubmed: 27584082
doi: 10.1002/mc.22550
D’Anjou F, Routhier S, Perreault JP, Latil A, Bonnel D, Fournier I, et al. Molecular validation of pace4 as a target in prostate cancer. Transl Oncol. 2011;4:157–72.
pubmed: 21633671
pmcid: 3104696
doi: 10.1593/tlo.10295
Maret D, Sadr MS, Sadr ES, Colman DR, Del Maestro RF, Seidah NG. Opposite roles of Furin and PC5A in N-cadherin processing. Neoplasia. 2012;14:880–92.
pubmed: 23097623
pmcid: 3479834
doi: 10.1593/neo.121250
Zhong M, Munzer JS, Basak A, Benjannet S, Mowla SJ, Decroly E, et al. The prosegments of furin and PC7 as potent inhibitors of proprotein convertases. In vitro and ex vivo assessment of their efficacy and selectivity. J Biol Chem. 1999;274:33913–20.
pubmed: 10567353
doi: 10.1074/jbc.274.48.33913
Zhou B, Gao S. Pan-cancer analysis of FURIN as a potential prognostic and immunological biomarker. Front Mol Biosci. 2021;8:1–15.
doi: 10.3389/fmolb.2021.648402
Zhao X, Subramanian S. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Res. 2017;77:817–22.
pubmed: 28159861
doi: 10.1158/0008-5472.CAN-16-2379
Brouwers B, Coppola I, Vints K, Dislich B, Jouvet N, Van Lommel L, et al. Loss of Furin in β-cells induces an mTORC1-ATF4 anabolic pathway that leads to β-cell dysfunction. Diabetes. 2021;70:492–503.
pubmed: 33277337
doi: 10.2337/db20-0474
Al Rifai O, Susan-Resiga D, Essalmani R, Creemers JWM, Seidah NG, Ferron M. In vivo analysis of the contribution of proprotein convertases to the processing of FGF23. Front Endocrinol (Lausanne). 2021;12:1–13.
doi: 10.3389/fendo.2021.690681
Jin W, Fuki IV, Seidah NG, Benjannet S, Glick JM, Rader DJ. Proprotein covertases are responsible for proteolysis and inactivation of endothelial lipase. J Biol Chem. 2005;280:36551–9.
pubmed: 16109723
doi: 10.1074/jbc.M502264200
Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C, et al. In vivo evidence that furin from hepatocytes inactivates PCSK9. J Biol Chem. 2011;286:4257–63.
pubmed: 21147780
doi: 10.1074/jbc.M110.192104
Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580–5.
doi: 10.1038/ng.2653
Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13.
pubmed: 28481359
pmcid: 5461196
doi: 10.1038/nm.4333