Membrane rafts segregate pro- from anti-apoptotic insulin-like growth factor-I receptor signaling in colon carcinoma cells stimulated by members of the tumor necrosis factor superfamily.
In the tumor microenvironment, autocrine/paracrine loops of insulin-like growth factors (IGFs) contribute to cancer cell survival. However, we report here that IGF-I can send contradictory signals that interfere with cell death induced by different ligands of the tumor necrosis factor (TNF) superfamily. IGF-I protected human colon carcinoma cells from TNF-alpha-induced apoptosis, but it enhanced the apoptotic response to anti-Fas antibody and TNF-related apoptosis inducing ligand stimulation. This proapoptotic effect of IGF-I, observed in several but not all tested colon cancer cell lines, was mediated via the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway. Furthermore, IGF-I receptors (IGF-IR) were located in and out of membrane lipid rafts and were tyrosine autophosphorylated in response to IGF-I. However, disruption of rafts by acute cholesterol depletion shifted IGF-IR to non-raft domains, abolished the IGF-I-mediated proapoptotic effect, and inhibited the IGF-I-dependent IRS-1 and Akt recruitment into and phosphorylation/activation within lipid rafts. Replenishing cell membranes with cholesterol reversed these effects. Activation of extracellular-regulated kinase-1/2 and p38 mitogen-activated protein kinase, which convey the IGF-I anti-apoptotic effect, occurred independently of lipid rafts. Thus, we propose that segregation of IGF-IR in and out of lipid rafts may dynamically regulate the pro- and anti-apoptotic effects of IGF-I on apoptosis induced by TNF superfamily members.
Remacle-Bonnet
Maryse
M
FRE CNRS 27.37, Faculté de Pharmacie, 27 Bd. Jean Moulin, 13385 Marseille Cedex 5, France. gilbert.pommier@pharmacie.univ-mrs.fr.
Garrouste
Françoise
F
Baillat
Gilbert
G
Andre
Frédéric
F
Marvaldi
Jacques
J
Pommier
Gilbert
G
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002277:Carcinoma / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000378:metabolism / Q000494:pharmacology*; D019014:fas Receptor / Q000276:immunology
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D002784:Cholesterol; D007334:Insulin-Like Growth Factor I; D008024:Ligands; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D019014:fas Receptor; C505653:TNFSF10 protein, human; C494918:AKT1 protein, human