title: Inhibition of the proprotein convertases represses the invasiveness of human primary melanoma cells with altered p53, CDKN2A and N-Ras genes.
abstract: BACKGROUND
  Altered tumor suppressor p53 and/or CDKN2A as well as Ras genes are frequently found in primary and metastatic melanomas. These alterations were found to be responsible for acquisition of invasive and metastatic potential through their defective regulatory control of metalloproteinases and urokinase genes.
  
  
  RESULTS
  Using primary human melanoma M10 cells with altered p53, CDKN2A and N-Ras genes, we found that inhibition of the proprotein convertases (PCs), enzymes involved in the proteolytic activation of various cancer-related protein precursors resulted in significantly reduced invasiveness. Analysis of M10 cells and their gastric and lymph node derived metastatic cells revealed the presence of all the PCs found in the secretory pathway. Expression of the general PCs inhibitor alpha1-PDX in these cells in a stable manner (M10/PDX) had no effect on the mRNA expression levels of these PCs. Whereas, in vitro digestion assays and cell transfection experiments, revealed that M10/PDX cells display reduced PCs activity and are unable to process the PCs substrates proIGF-1R and proPDGF-A. These cells showed reduced migration and invasion that paralleled decreased gelatinase MMP-2 activity and increased expression and secretion of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Furthermore, these cells showed decreased levels of urokinase-type plasminogen activator receptor (uPAR) and increased levels of plasminogen activator inhibitor-1 (PAI-1).
  
  
  CONCLUSIONS
  Taken together, these data suggest that inhibition of PCs activity results in decreased invasiveness of primary human melanoma cells despite their altered p53, CDKN2A and N-Ras genes, suggesting that PCs may serve as novel therapeutic targets in melanoma.
authors.affiliation: INSERM, UMRS940, Equipe Avenir, Institut de Génétique Moléculaire, Hôpital Saint-Louis, Université Paris 7, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Lalou
authors.forename: Nathalie
authors.initials: N
authors.lastname: Scamuffa
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
authors.forename: Francois
authors.initials: F
authors.lastname: Plassa
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Podgorniak
authors.forename: Nadem
authors.initials: N
authors.lastname: Soufir
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumaz
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.forename: Nicole
authors.initials: N
authors.lastname: Basset-Seguin
authors.forename: Abdel-Majid
authors.initials: AM
authors.lastname: Khatib
mesh_terms: D019942:Genes, p16; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D009361:Neoplasm Invasiveness; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D013270:Stomach / Q000473:pathology; D014407:Tumor Cells, Cultured; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D000515:alpha 1-Antitrypsin; C113421:alpha 1-antitrypsin Portland; D043484:Proprotein Convertases; D020778:Matrix Metalloproteinase 2
references.citation: J Biol Chem. 2002 Mar 29;277(13):10804-12
references.pmid: 11792711
references.citation: Oncogene. 2004 Mar 25;23(13):2330-8
references.pmid: 14743206
references.citation: Med Res Rev. 2007 Sep;27(5):631-48
references.pmid: 17019676
references.citation: Cancer Res. 2003 Apr 1;63(7):1458-63
references.pmid: 12670890
references.citation: BMC Cancer. 2005 Nov 17;5:149
references.pmid: 16293189
references.citation: Cancer Res. 2000 Apr 1;60(7):1800-4
references.pmid: 10766161
references.citation: Oncogene. 1997 Oct 23;15(17):2049-57
references.pmid: 9366522
references.citation: J Biol Chem. 2001 Aug 17;276(33):30686-93
references.pmid: 11402025
references.citation: Cancer Res. 1996 Dec 1;56(23):5475-83
references.pmid: 8968104
references.citation: J Clin Invest. 2008 Jan;118(1):352-63
references.pmid: 18064302
references.citation: Mol Cell Biol. 2000 Aug;20(16):5828-39
references.pmid: 10913166
references.citation: J Biol Chem. 1989 Oct 15;264(29):17374-8
references.pmid: 2793861
references.citation: Cell Oncol. 2007;29(4):289-99
references.pmid: 17641413
references.citation: J Biol Chem. 1999 Apr 23;274(17):11535-40
references.pmid: 10206959
references.citation: Infect Immun. 1996 Feb;64(2):524-7
references.pmid: 8550202
references.citation: Melanoma Res. 1999 Jun;9(3):279-91
references.pmid: 10465584
references.citation: J Biol Chem. 2008 Jul 11;283(28):19570-80
references.pmid: 18469003
references.citation: J Cell Physiol. 2006 Jul;208(1):246-52
references.pmid: 16575904
references.citation: Int J Cancer. 1997 Jul 17;72(2):241-7
references.pmid: 9219827
references.citation: J Mol Med (Berl). 2005 Nov;83(11):856-64
references.pmid: 16133424
references.citation: EMBO J. 1997 May 1;16(9):2319-32
references.pmid: 9171346
references.citation: J Clin Invest. 1993 Mar;91(3):1183-90
references.pmid: 8450047
references.citation: Int J Cancer. 2009 Jan 1;124(1):16-26
references.pmid: 18814281
references.citation: Am J Surg Pathol. 2008 Jan;32(1):36-44
references.pmid: 18162768
references.citation: Am J Respir Cell Mol Biol. 2008 Sep;39(3):364-72
references.pmid: 18390474
references.citation: Cancer Res. 2007 Oct 1;67(19):9030-4
references.pmid: 17909005
references.citation: Mol Carcinog. 2005 Nov;44(3):151-61
references.pmid: 16167351
references.citation: Pathology. 2006 Aug;38(4):287-301
references.pmid: 16916716
references.citation: Cancer Res. 1994 Aug 15;54(16):4547-52
references.pmid: 8044805
references.citation: Genes Dev. 1995 Apr 15;9(8):935-44
references.pmid: 7774811
references.citation: Am J Pathol. 2002 Jun;160(6):1921-35
references.pmid: 12057895
references.citation: Mol Cell Biol. 1997 Nov;17(11):6330-8
references.pmid: 9343394
references.citation: Oncogene. 2002 Jan 3;21(1):87-95
references.pmid: 11791179
references.citation: Glia. 2008 Jun;56(8):917-24
references.pmid: 18383343
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10326-31
references.pmid: 11517338
references.citation: Curr Med Chem. 2007;14(4):387-91
references.pmid: 17305541
references.citation: Nat Rev Cancer. 2002 Aug;2(8):594-604
references.pmid: 12154352
references.citation: Hum Reprod. 2008 Oct;23(10):2273-81
references.pmid: 18635530
references.citation: Methods Mol Biol. 2009;487:267-81
references.pmid: 19301652