Reversal of 5-fluorouracil resistance by EGCG is mediate by inactivation of TFAP2A/VEGF signaling pathway and down-regulation of MDR-1 and P-gp expression in gastric cancer

// Hongsheng Tang 1, 2, * , Lisi Zeng 2, * , Jiahong Wang 2 , Xiangliang Zhang 2 , Qiang Ruan 2 , Jin Wang 2 , Shuzhong Cui 2 and Dinghua Yang 1 1 Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China 2 Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong Province, China * These authors have contributed equally to this work and should be considered co-first authors Correspondence to: Dinghua Yang, email: 13600039623@163.com Shuzhong Cui, email: cuishuzhong@126.com Keywords: EGCG, gastric cancer, drug resistance, 5-fluorouracil, VEGF Received: December 28, 2016      Accepted: June 24, 2017      Published: September 06, 2017 ABSTRACT The effect of 5-fluorouracil (5-FU) chemotherapy for gastric cancer (GC) is limited by drug-resistance. To conquer this drug-resistance, various treatments including combination therapy have been used, but the overall survival has not been improved yet. In our current study, 5-FU resistant GC cells, SGC7901/FU and MGC803/FU, were established by long term exposure to 5-FU, and the proliferation capability of these resistant cells was verified to be reduced. The drug related proteins, MDR1 and P-gp were up-regulated in resistant cells compared to the parental cells. We further found proliferation and tumor growth suppressed effects of epigallocatechin gallate (EGCG), which is the predominant polyphenolic catechin constituent in green tea, on both the 5-FU resistant cells and the SGC7901/FU xenograft. Furthermore, an interesting results showed that reversal of 5-FU resistance of GC cells by EGCG treatment in vivo and in vitro . In the molecular study, We also found that EGCG suppressed the expression of both MDR-1 and P-gp at mRNA and protein levels in vivo and in vitro . Western blot and ELISA assay revealed that EGCG was able to inhibit VEGF secretion and expression, and its up-stream signal regulator, transcription factor activator protein 2A (TFAP2A) was also down-regulated by EGCG, our results indicated that TFAP2A/VEGF axis is one of the critical pathway inhibited by EGCG for cell proliferation and 5-FU resistance. Taken together, our data suggested that EGCG inhibits GC growth and reverses 5-FU resistance of GC through inactivation of TFAP2A/VEGF pathway and down-regulation of MDR-1 and P-gp expression.