Inhibition of the Insulin-Like Growth Factor I Receptor by Epigallocatechin Gallate Blocks Proliferation and Induces the Death of Ewing Tumor Cells

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. Mol Cancer Ther; 9(5); 1396-407. ©2010 AACR.

The molecular genetics underlying basal cell carcinoma pathogenesis and links to targeted therapeutics

“…Recently, Kang and colleagues 49 have demonstrated how the major antioxidant catechin in green tea, epigallocatechin gallate (EGCG), can influence the BCL2 family. Specifically, EGCG can increase the expression of the pro-apoptotic BAX (also known as BCL2-associated X protein) and decrease expression of pro-proliferative BCL2.…”

“…Therefore, while the SHH pathway can influence BCL2 proteins favoring tumorigenesis, these effects could be attenuated by a green tea antioxidant. 49 Other avenues for therapeutic exploration include FOXM1, another molecular target that lies downstream of the SHH pathway. Recently Bhat, Halasi, and Gartel 50 have shown that the forkhead box oncogenic transcription factor may be a targeted by the thiazole antibiotics, siomycin A, and thiostrepton.…”

Epigallocatechin-3-Gallate Suppresses IGF-I-Induced Lipogenesis and Cytokine Expression in SZ95 Sebocytes

“…It has various bioactivities, including anti-oxidative, anti-inflammatory, anti-bacterial, anti-obesity, and anti-mutagenic effects (Cabrera et al, 2006). Additionally, it inhibits proliferation of various cells, probably by blocking IGF/IGF-IR-related autocrine or paracrine loops (Shimizu et al, 2008;Kang et al, 2010). Some investigators have reported that EGCG has clinical efficacy as an acne therapeutic agent (Elsaie et al, 2009;Mahmood et al, 2010).…”

Role of Ku70 and Bax in epigallocatechin-3-gallate-induced apoptosis of A549 cells in vivo

“…The Bcl-xl protein and other family members locate at the intracellular organelles, including the endoplasmic reticulum and the outer mitochondrial and nuclear membranes, where they modulate responses to diverse death stimuli (27). In Ewing family tumor (EFT) cells, apoptosis by EGCG correlated with altered expression of Bcl-2 family proteins, including increased expression of proapoptotic Bax and decreased expression of prosurvival Bcl-2, Bcl-xl and Mcl-1 proteins (28). In addition, EGCG enhanced apoptosis as demonstrated by an increase in the Bax:Bcl-xl ratio, cleavage of procaspases 3, 8 and 9 and poly (adenosine diphosphate ribose) polymerase and accumulation of subG1 cells in skin cancer cells (29).…”