Autocrine heregulin generates growth factor independence and blocks apoptosis in colon cancer cells.
The aim of this study was to determine whether constitutive ErbB2 activation controls growth and apoptosis in colon cancer cells. Growth arrested GEO cells showed constitutive activation of ErbB2 in the absence of exogenous growth factors or serum supplementation. Higher levels of heregulin and ErbB2 activation were observed in the growth-arrested state and cell cycle re-entry was independent of exogenous growth factors. Blockade of ErbB2 activation by heregulin neutralizing antibodies and by AG879 resulted in prevention of cell cycle re-entry. This indicated that autocrine heregulin activity was responsible for growth factor independence and for cell cycle re-entry. Activation of ErbB2 was the result of heregulin mediated interaction with ErbB3 and generated downstream activation of the ERK and the PI3K/AKT pathways. Heregulin neutralizing antibody treatment of growth arrested GEO cells also generated apoptosis as reflected by PARP cleavage and DNA fragmentation indicating a cell survival signal was also induced by the constitutively activated ErbB2. The activation of AKT but not the MAPK pathway was responsible for cell survival in these cells.
Venkateswarlu
Srinivas
S
Department of Surgery, University of Texas Health Science Center at San Antonio, Texas, TX 78284, USA.
Dawson
Dawn M
DM
St Clair
Patricia
P
Gupta
Anjana
A
Willson
James K V
JK
Brattain
Michael G
MG
D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000502:physiology*; D019898:Autocrine Communication; D002453:Cell Cycle / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology*; D003470:Culture Media / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D053938:DNA Fragmentation; D019281:Dimerization; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018734:Genes, erbB-2; D006133:Growth Substances / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D020890:Neuregulin-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009500:Neutralization Tests; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D020893:Receptor, ErbB-3 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D002867:Chromones; D003470:Culture Media; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006133:Growth Substances; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020893:Receptor, ErbB-3; D020123:Sirolimus; D016211:Transforming Growth Factor alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one