Abstract
Epigallocatechin-3-O-gallate (EGCG) is one of the major bioactive compounds known to be present in green tea. We previously reported that EGCG shows selective toxicity through activation of the protein kinase B (Akt)/cyclic guanosine monophosphate (cGMP)/acid sphingomyelinase (ASM) axis via targeting its receptor 67-kDa laminin receptor (67LR), which is overexpressed in cancer. However, little is known about upstream mechanisms of EGCG-elicited ASM activation. In this study we show that the proto-oncogene tyrosine-protein kinase Src, also known as c-src, plays a crucial role in the anticancer effect of EGCG. We showed that EGCG elicits phosphorylation of Src at Tyr 416, a crucial phosphorylation site for its activity, and that the pharmacological inhibition of Src impedes the upstream events in EGCG-induced cell death signaling including upregulation of Akt activity, increase in cGMP levels, and activation of ASM. Moreover, focal adhesion kinase (FAK), which is involved in the phosphorylation of Src, is colocalized with 67LR. EGCG treatment enhanced interaction of FAK and 67LR. Consistent with these findings, pharmacological inhibition of FAK significantly neutralized EGCG-induced upregulation of Akt activity and activation of ASM. Taken together, FAK/Src play crucial roles in the upstream signaling of EGCG.
Highlights
Multiple myeloma is one of the hematologic cancers that develop in mature B cells [1]
Several advances have been made in the treatment of multiple myeloma; the treatment is still difficult as multiple myeloma is chemoresistant and as patients with multiple myeloma are is still difficult as multiple myeloma is chemoresistant and as patients with multiple myeloma are often old and chemotherapeutic agents have adverse effects on them
Several clinical and preclinical studies have indicated that green tea polyphenol EGCG could be a potential candidate for the treatment of B cell lymphoma and multiple myeloma because it has selective toxicity and is well tolerated [8,20]
Summary
Multiple myeloma is one of the hematologic cancers that develop in mature B cells [1]. Several prominent advances have been made in chemotherapy for multiple myeloma, and overall survival has been extended from 3 to 6 years in the past two decades [2]. Multiple myeloma is still a difficult hematopoietic malignancy because of its chemoresistant character and because patients with multiple myeloma are typically older and adverse effects induced by anticancer agents pose difficulties in treatment. Several epidemiological studies indicate negative correlation between green tea consumption and the risk of cancer. Naganuma et al demonstrated that the multivariate-adjusted hazard ratio of hematologic malignancies for individuals consuming 5 cups/day or more of green tea compared with those consuming less than 1 cup/day was 0.58 (95% confidence interval: 0.37, 0.89)
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