Enhancing the Therapeutic Effects of Ethyl Pyruvate on Gastric Cancer through Knockdown of YAP1 Expression

Abstract

Yes-associated protein (YAP) plays a critical role in tumor formation and malignancy of many cancers and has been shown to be the important therapeutic target. Ethyl pyruvate (EP), a stable lipophilic pyruvate derivative, is a potent inhibitor of high mobility group box-B1 (HMGB1) release and exerts significant anti-inflammatory activities. Previously, we reported the high expression of YAP1 and the antitumor effects of EP in gastric cancer (GC). However, whether small hairpin RNA (shRNA)-mediated knockdown of YAP1 expression enhances the antitumor effects of EP on GC is elusive. After GC SGC-7901 cells infected with lentivirus-mediated YAP1 shRNA vector were treated with 20mmol/L EP, the expression levels of HMGB1, receptor for advanced glycation endproducts (RAGE) and Protein kinase B (AKT) were identified by Real-time PCR and Western blot assays. Cell proliferative activities and independent growth were examined by MTT and colony formation assays, and their migration and metastasis were evaluated by wound-healing and Transwell assays. Cell apoptosis and cycle distribution were assessed by flow cytometry. As a result, EP coupled with YAP1 shRNA significantly decreased the expression levels of HMGB1, RAGE and AKT, inhibited the proliferative activities and migration and metastasis capabilities, and induced apoptosis and cycle arrest in GC cells compared with the single EP treatment. Taken together, knockdown of YAP1 enhances the inhibitory effects of EPon GC cells through inhibition of the HMGB1-RAGE and AKT pathways, and this may provide an attractive strategy for the treatment of GC.