Autocrine stimulation by insulin-like growth factor I is involved in the growth, tumorigenicity and chemoresistance of human esophageal carcinoma cells.
Insulin-like growth factor I (IGF-I) receptor (IGF-IR)-mediated signals are known to be involved in cell growth and transformation and prevention of apoptosis. In this study, we demonstrated the coexpression of IGF-I and IGF-IR in human esophageal carcinoma tissues. We also demonstrated the IGF-I autocrine system in esophageal carcinoma cell lines. Both the CE48T/VGH and CE81T/VGH cell lines showed proliferative responses to IGF-I stimulation. Autokinase activity of IGF-IR in these cells can be triggered by the exogenous addition of IGF-I. In addition, an IGF-I peptide antagonist, JB1, specifically inhibited ligand-induced receptor autophosphorylation in a dose-dependent manner. Under serum-free conditions, JB1 also reduced the degree of IGF-IR phosphorylation and cell numbers. Furthermore, the addition of JB1 decreased the number of CE81T/VGH colonies formed in methyl cellulose agar and the size and the incidence of tumors which grew in mice with severe combined immunodeficiency. These results imply that an IGF-I autocrine system in human esophageal carcinoma cells could stimulate tumor growth. Finally, we found that IGF-I prevented the apoptosis of CE81T/VGH cells induced by chemotherapeutic drugs, such as cisplatin, 5-fluorouracil and camptothecin. Thus, interruption of IGF-IR function may provide a way to retard tumor growth and increase the sensitivity of esophageal carcinoma to chemotherapy.
Liu
Young-Chau
YC
Department of Medical Research and Education, Veterans General Hospital-Taipei, Taipei, Taiwan, ROC.
Leu
Chuen-Miin
CM
Wong
Fen-Hwa
FH
Fong
Wan-Shung
WS
Chen
Shan-Chun
SC
Chang
Chungming
C
Hu
Cheng-po
CP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000737:chemistry* / Q000188:drug therapy; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1