title: Concomitant cell growth and differentiation are dependent on erbB1 and integrin activation in an autonomously surviving colon adenocarcinoma: involvement of autocrine amphiregulin secretion.
abstract: 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.
authors.affiliation: FRE CNRS 2737, Faculté de Pharmacie, Université Aix-Marseille II, 27 Bd Jean Moulin, 13385 Marseille, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Picihard
authors.forename: Yolande
authors.initials: Y
authors.lastname: Berthois
authors.forename: Monique
authors.initials: M
authors.lastname: Roccabianca
authors.forename: Charles
authors.initials: C
authors.lastname: Prévôt
authors.forename: Marcel
authors.initials: M
authors.lastname: Sarrazin
authors.forename: Henri
authors.initials: H
authors.lastname: Portugal
authors.forename: Shant
authors.initials: S
authors.lastname: Kumar
authors.forename: Pat
authors.initials: P
authors.lastname: Kumar
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rognoni
mesh_terms: 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
chemical_list: 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