Beta-casein-derived peptides, produced by bacteria, stimulate cancer cell invasion and motility.
In colon cancer, enteric bacteria and dietary factors are major determinants of the microenvironment but their effect on cellular invasion is not known. We therefore incubated human HCT-8/E11 colon cancer cells with bacteria or bacterial conditioned medium on top of collagen type I gels. Listeria monocytogenes stimulate cellular invasion through the formation of a soluble motility-promoting factor, identified as a 13mer beta-casein-derived peptide (HKEMPFPKYPVEP). The peptide is formed through the combined action of Mpl, a Listeria thermolysin-like metalloprotease, and a collagen-associated trypsin-like serine protease. The 13mer peptide was also formed by tumour biopsies isolated from colon cancer patients and incubated with a beta-casein source. The pro- invasive 13mer peptide-signalling pathway implicates activation of Cdc42 and inactivation of RhoA, linked to each other through the serine/threonine p21- activated kinase 1. Since both changes are necessary but not sufficient, another pathway might branch upstream of Cdc42 at phosphatidylinositol 3-kinase. Delta opioid receptor (deltaOR) is a candidate receptor for the 13mer peptide since naloxone, an deltaOR antagonist, blocks both deltaOR serine phosphorylation and 13mer peptide-mediated invasion.
Oliveira
Maria José
MJ
Laboratory of Experimental Cancerology, Gent University Hospital, De Pintelaan 185, Gent, Belgium.
Van Damme
Jozef
J
Lauwaet
Tineke
T
De Corte
Veerle
V
De Bruyne
Georges
G
Verschraegen
Gerda
G
Vaneechoutte
Mario
M
Goethals
Marc
M
Ahmadian
Mohammad Reza
MR
Müller
Oliver
O
Vandekerckhove
Joël
J
Mareel
Marc
M
Leroy
Ancy
A
D001426:Bacterial Proteins; D002364:Caseins / Q000235:genetics*; D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism; D006801:Humans; D008089:Listeria monocytogenes / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D001426:Bacterial Proteins; D002364:Caseins; D024042:Collagen Type I; D008666:Metalloendopeptidases; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D017480:Receptors, sigma; D020764:cdc42 GTP-Binding Protein; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C515903:PAK1 protein, human; C080367:mpl protein, Listeria monocytogenes