Abstract
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.
Highlights
It is widely reported that catechin derivatives contained in green tea have antineoplastic activity [1]
TC71 cells were less sensitive than TC32 cells but still showed significant cytotoxicity at a 50 μmol/L concentration. The reason for this discrepancy between TC32 and TC71 cells remains unknown. These results indicate that Ewing family tumors (EFT) cells are sensitive to epigallocatechin gallate (EGCG) treatment at concentrations that are ineffective at inducing cytotoxicity in normal Human brain microvascular endothelial cells (HBMECs) cells
The percentage of apoptotic TC32 cells increased in a dose-dependent fashion, with ∼90% apoptotic cells after treatment with 25 μmol/L EGCG. These results indicate that the predominant effect of EGCG on EFT cells may be through the induction of apoptosis, with a possible minor effect in inducing cell cycle arrest
Summary
It is widely reported that catechin derivatives contained in green tea have antineoplastic activity [1]. Other potential targets for inhibition by EGCG include signaling by NF-κB in colon cancer cells [5], cyclooxygenase-2 expression and activity [18, 19], and matrix metalloproteinases such as matrix metalloproteinase-2 and matrix metalloproteinase-9 that are involved in tumor cell invasion and metastasis [20]. This broad spectrum of mechanistic possibilities for the antineoplastic actions of EGCG supports the need for further studies to identify its relevant molecular targets. This agent may have different targets depending on the cellular context and it will be essential to identify specific targets in a given tumor type to optimize potential clinical benefits of EGCG for that disease
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