Synergistic growth inhibition of squamous cell carcinoma of the head and neck by erlotinib and EGCG: the role of p53-dependent inhibition of nuclear factor-kappaB

• Type of Material: Article
• Authors: A R M Ruhul Amin, Emory University; Fadlo Khuri, Emory University; Zhuo (Georgia) Chen, Emory University; Dong M Shin, Emory University
• Language: English
• Date: 2009-06
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009, American Association for Cancer Research
• Final Published Version (URL): http://cancerpreventionresearch.aacrjournals.org/content/2/6/538.long
• Title of Journal or Parent Work: Cancer Prevention Research
• ISSN: 1940-6207
• Volume: 2
• Issue: 6
• Start Page: 538
• End Page: 545
• Grant/Funding Information: This work was supported by grants from the NIH (P50 CA128613, U01 CA101244, and R01 CA112643). DMS, GC and FRK are Distinguished Cancer Scholars of the Georgia Cancer Coalition (GCC).
• Keywords: molecular targets; p53; Chemoprevention; EGFR-TKI
• Research Categories: Health Sciences, Oncology

Abstract

We have previously reported that the green tea polyphenol epigallocatechin-3-gallate (EGCG) and the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) erlotinib had synergistic growth inhibitory effects in cell culture and a nude mouse xenograft model of squamous cell carcinoma of the head and neck (SCCHN). However, the mechanism of their anti-tumor synergism is not fully understood. In the current study, we investigate the mechanism of their synergistic growth inhibitory effects. The treatment of SCCHN cell lines with erlotinib time-dependently increased the expression of cell cycle regulatory proteins p21 and p27 and apoptosis regulatory protein Bim. EGCG alone had very little or no effect on the expression of these proteins among the cell lines. However, simultaneous treatment with EGCG and erlotinib strongly inhibited erlotinib-induced expression of p21 and p27 without affecting the expression of Bim. Moreover, erlotinib increased the expression of p53 protein, the ablation of which by shRNA strongly inhibited EGCG- and erlotinib-mediated growth inhibition and the expression of 21, p27 and Bim. In addition, combined treatment with erlotinib and EGCG inhibited the protein level of p65 subunit of NF-κB and its transcriptional target Bcl-2, but failed to do so in cells with ablated p53. Taken together our results, for the first time, suggest that erlotinib treatment activates p53, which plays a critical role in synergistic growth inhibition by erlotinib and EGCG via inhibiting NK-κB signaling pathway. Characterizing the underlying mechanisms of EGCG and erlotinib synergism will provide an important rationale for chemoprevention or treatment trials using this combination.