Degradation of insulin-like growth factor-I receptor occurs via ubiquitin-proteasome pathway in human lung cancer cells.
Insulin-like growth factor-I receptor (IGF-IR) is often overexpressed in malignant tumors, and is involved in the establishment and maintenance of malignant phenotypes. Tyrosine kinase receptor endocytosis is commonly triggered by ligand binding and occurs via clathrin-coated vescicles that transfer the receptor to the lysosome system for degradation. Our study aims at the evaluation of the mechanisms involved in IGF-IR downregulation in neoplastic (Npl) and non-neoplastic (non-Npl) cells. Exposure to insulin-like growth factor-I (IGF-I) of human lung adenocarcinoma cell lines (A549 and H1299) triggers IGF-IR ubiquitination and internalization processes that require energy and are preceded by the phosphorylation of receptor tyrosines. Differently from other plasma membrane substrates of the ubiquitin system, IGF-IR is degraded mostly by the proteasome in these tumor cell lines. The degradation is inhibited by lactacystin and unaffected by lysosomal inhibitors such as bafilomycin A1 and NH(4)Cl. IGF-IR is processed in a similar manner also in fresh specimens of human lung tumors, while it requires active lysosomal functions in non-Npl human lung tissues. These results suggest that the degradation routes of ubiquitinated IGF-IR diverge in normal and Npl cells, and further support the involvement of IGF-IR signaling in cancer. Such a different route for IGF-IR processing might take place sometime during development, since both proteasome and lysosome pathways are active in fetal lung human fibroblasts, IMR90 cells.
Carelli
Stephana
S
Laboratory of Pharmacology, Department of Medicine, Surgery, and Dentistry, University of Milan, Milan, Italy.
Di Giulio
Anna Maria
AM
Paratore
Simona
S
Bosari
Silvano
S
Gorio
Alfredo
A
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry; D025801:Ubiquitin / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D025801:Ubiquitin; C067713:lactacystin; D014443:Tyrosine; D017526:Receptor, IGF Type 1; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine