Inhibition of the insulin-like growth factor I receptor by epigallocatechin gallate blocks proliferation and induces the death of Ewing tumor cells.
The insulin-like growth factor I receptor (IGFIR) has emerged as a key therapeutic target in many human malignancies, including childhood cancers such as Ewing family tumors (EFT). In this study, we show that IGFIR is constitutively activated in EFTs and that the major catechin derivative found in green tea, (-)-epigallocatechin gallate (EGCG), can inhibit cell proliferation and survival of EFT cells through the inhibition of IGFIR activity. Treatment of EFT cell lines with EGCG blocked the autophosphorylation of IGFIR tyrosine residues and inhibited its downstream pathways including phosphoinositide 3-kinase-Akt, Ras-Erk, and Jak-Stat cascades. EGCG treatment was associated with dose- and time-dependent inhibition of cellular proliferation, viability, and anchorage-independent growth, as well as with the induction of cell cycle arrest and apoptosis. Apoptosis in EFT cells by EGCG correlated with altered expression of Bcl-2 family proteins, including increased expression of proapoptotic Bax and decreased expression of prosurvival Bcl2, Bcl-XL, and Mcl-1 proteins. Our results provide further evidence that IGFIR is an attractive therapeutic target in EFTs and that EGCG is an effective inhibitor of this receptor tyrosine kinase. EGCG may be a useful agent for targeting IGFIR, either alone or in combination, with other potentially more toxic IGFIR inhibitors for the management of EFTs.
Kang
Hyung-Gyoo
HG
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.
Jenabi
Jasmine M
JM
Liu
Xian Fang
XF
Reynolds
C Patrick
CP
Triche
Timothy J
TJ
Sorensen
Poul H B
PH
D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000473:pathology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000473:pathology*
D016588:Anticarcinogenic Agents; D002392:Catechin; C045651:epigallocatechin gallate; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051058:Oncogene Protein v-akt