Induction of tumor suppression and glandular differentiation of A549 lung carcinoma cells by dominant-negative IGF-I receptor.
Overexpression or activation of insulin-like growth factor I receptor (IGF-IR) has been observed in many human cancers including breast, lung, colon and gastric carcinomas. We demonstrate that inhibition of the endogenous insulin-like growth factor I receptor by stable expression of a dominant-negative IGF-IR represses the transforming activity in vitro and tumorigenicity of human lung carcinoma cells A549 in vivo. The suppression of tumorigenicity in nude mice is correlated with the induction of glandular differentiation. In addition, functional inhibition of the endogenous receptor dramatically increases the sensitivity of A549 cells to a variety of apoptotic signals including UV irradiation and proteasome inhibitors. These effects are due to the formation of a stable heterocomplex of the dominant-negative receptor with the endogenous wild type receptor which reduces the kinase activity of the latter by twofold. Thus, inhibition of the IGF-IR signaling pathway not only suppresses tumorigenicity but also enhances sensitivity to apoptosis-inducing agents. Antagonizing IGF-IR signaling by promoting tumor differentiation and enhancing sensitivity to apoptotic death are potential cancer therapeutic approaches.
Jiang
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Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York University Medical Center, 550 First Avenue, MSB 147, New York, NY 10016, USA.
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Yie
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Tchou-Wong
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D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015197:Carcinogenicity Tests; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics / Q000528:radiation effects; D003546:Cysteine Endopeptidases / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D016147:Genes, Tumor Suppressor; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000187:drug effects; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; C067713:lactacystin; D017526:Receptor, IGF Type 1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine