Concomitant cell growth and differentiation are dependent on erbB1 and integrin activation in an autonomously surviving colon adenocarcinoma: involvement of autocrine amphiregulin secretion.
In normal colon epithelium, cell proliferation is followed by cell differentiation. The purpose of this work was to investigate, in the HT29-D4 colon adenocarcinoma cell line, the occurrence of a temporal sequence of changes in cell proliferation and differentiation, the role of autocrine EGF family ligands and to determine which transduction pathway(s) are involved in these processes. In a medium lacking both growth factor and serum, HT29-D4 cells secreted amphiregulin (AR), which was shown to be strongly involved in cell adhesion, growth and differentiation. In the main, integrins alpha2beta1 and alphavbeta6 intervened in these processes. Using tyrphostins, it was demonstrated that AR involvement was mediated through the ErbB1/ERK1,2 and ErbB1/FAK pathways. These signalling molecules were directly involved in pRb inhibition and, thus, in cyclin A expression. Concomitantly, colon differentiation markers were also expressed. Furthermore, terminal cell maturation resulted in a colon absorptive cell with strong polarisation, the growth of which was inhibited by tyrphostin and an ERK1,2 inhibitor. It was concluded that in a colon adenocarcinoma, cell proliferation and differentiation can occur concomitantly and that these deregulated processes are controlled by autocrine secretion through the ErbB1/ERK1,2 and FAK pathways.
Picihard
Veronique
V
FRE CNRS 2737, Faculté de Pharmacie, Université Aix-Marseille II, 27 Bd Jean Moulin, 13385 Marseille, France.
Berthois
Yolande
Y
Roccabianca
Monique
M
Prévôt
Charles
C
Sarrazin
Marcel
M
Portugal
Henri
H
Kumar
Shant
S
Kumar
Pat
P
Rognoni
Jean-Baptiste
JB
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D000469:Alkaline Phosphatase / Q000096:biosynthesis; D066258:Amphiregulin; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016213:Cyclins / Q000096:biosynthesis; D066255:EGF Family of Proteins; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D013394:Sucrase-Isomaltase Complex / Q000096:biosynthesis; D020032:Tyrphostins / Q000494:pharmacology
C587848:AREG protein, human; D066258:Amphiregulin; D000951:Antigens, Neoplasm; D016213:Cyclins; D066255:EGF Family of Proteins; D006023:Glycoproteins; D038982:Integrin alpha2beta1; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D011799:Quinazolines; D016160:Retinoblastoma Protein; D020032:Tyrphostins; C073878:integrin alphavbeta6; C026615:villin; C101044:RTKI cpd; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000469:Alkaline Phosphatase; D013394:Sucrase-Isomaltase Complex