Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin

• Published in: Cancer biology & therapy 2013-09, Vol.14 (9), p.833-839
• Main Authors: Yao, Jun, Qian, Cuijuan, Shu, Ting, Zhang, Xin, Zhao, Zhiqiang, Liang, Yong
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; apoptosis; Apoptosis - drug effects; beta Catenin - metabolism; Cell Line, Tumor; DAPT; Dipeptides - administration & dosage; Down-Regulation; ERK; Female; Flavonoids - administration & dosage; gastric cancer; Humans; Male; MAP Kinase Signaling System; Mice, Nude; Middle Aged; Notch1; PD98059; Receptor, Notch1 - metabolism; Research Paper; Stomach Neoplasms - drug therapy; Wnt Proteins - metabolism; β-catenin
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.25332

γ-secretase inhibitors (GSIs), the indirect inhibitors of Notch, are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies, but little is known about their effects on gastric cancer. In this study, we demonstrate that DAPT, a potent GSI, was effective to inhibit γ-secretase activity in gastric cancer (GC) cell lines that contained a fragment with approximately the size of the Notch1 intracellular domain (NICD), but was limited in their ability to induce apoptosis. However, activation of extracellular signal-regulated kinase (ERK)1/2 upon DAPT treatment was detected. Selective inhibition of ERK1/2 activation dramatically sensitized GC cells to apoptosis via downregulating β-catenin signaling in these GC cells. Notably, in a xenograft mouse tumor model, combination therapy using ERK inhibitor PD98059 plus DAPT yielded additive antitumor effects as compared with either agent alone. Taken together, these data demonstrated that γ-secretase inhibition combined with ERK1/2 inhibitor enhances cell death in GC cells partly through downregulation of WNT/β-catenin pathways.