(-)-Epigallocatechin gallate induces Fas/CD95-mediated apoptosis through inhibiting constitutive and IL-6-induced JAK/STAT3 signaling in head and neck squamous cell carcinoma cells.
In this study, we examined the effects of several plant-derived natural compounds on head and neck squamous cell carcinoma (HNSCC) cells. The results revealed that (-)-epigallocatechin gallate (EGCG) demonstrated the most efficient cytotoxic effects on HNSCC cells. We then investigated the underlying molecular mechanism for the potent proapoptotic effect of EGCG on HNSCC. Cell apoptosis was observed in the EGCG-treated SAS and Cal-27 cells in a time- and dose-dependent manner. In concert with the caspase-8 activation by EGCG, an enhanced expression in functional Fas/CD95 was identified. Consistent with the increased Fas/CD95 expression, a drastic decrease in the Tyr705 phosphorylation of STAT3, a known negative regulator of Fas/CD95 transcription, was shown within 15 min in the EGCG-treated cells, leading to downregulation of the target gene products of STAT3, such as bcl-2, vascular endothelial growth factor (VEGF), mcl-1, and cyclin D1. An overexpression in STAT3 led to resistance to EGCG, suggesting that STAT3 was a critical target of EGCG. Besides inhibiting constitutive expression, EGCG also abrogated the interleukin-6 (IL-6)-induced JAK/STAT3 signaling and further inhibited IL-6-induced proliferation on HNSCC cells. In comparison with apigenin, curcumin, and AG490, EGCG was a more effective inhibitor of IL-6-induced proliferation on HNSCC cells. Overall, our results strongly suggest that EGCG induces Fas/CD95-mediated apoptosis through inhibiting constitutive and IL-6-induced JAK/STAT3 signaling. This mechanism may be partially responsible for EGCG's ability to suppress proliferation of HNSCC cells. These findings provide that EGCG may be useful in the chemoprevention and/or treatment of HNSCC.
School of Pharmacy, College of Medicine, College of Pharmacy, China Medical University, Taichung, Taiwan.
Hui-Yi
HY
Lin
Shin-Chen
SC
Hou
Shi-Chen
SC
Chen
Ming-Ching
MC
Kao
Chien-Chih
CC
Yu
Shinji
S
Funayama
Chi-Tang
CT
Ho
Tzong-Der
TD
Way
D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck
D053222:Fas Ligand Protein; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D002392:Catechin; C045651:epigallocatechin gallate