title: Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin.
abstract: 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.
authors.affiliation: Institute of Tumor; School of Medicine; Taizhou University; Taizhou, Zhejiang P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Insitute of Gastroenterology; Sir Run Run Shaw Hospital; Zhejiang University; Hangzhou, Zhejiang P.R. China.
authors.forename: Cuijuan
authors.initials: C
authors.lastname: Qian
authors.affiliation: Institute of Tumor; School of Medicine; Taizhou University; Taizhou, Zhejiang P.R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Shu
authors.affiliation: Department of Gastroenterology; Taizhou Municipal Hospital; Taizhou, Zhejiang P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Tumor; School of Medicine; Taizhou University; Taizhou, Zhejiang P.R. China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Institute of Tumor; School of Medicine; Taizhou University; Taizhou, Zhejiang P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000008:administration & dosage; D015536:Down-Regulation; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D051881:Receptor, Notch1 / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D004151:Dipeptides; D005419:Flavonoids; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051881:Receptor, Notch1; D051153:Wnt Proteins; D051176:beta Catenin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: DAPT; ERK; Notch1; PD98059; apoptosis; gastric cancer; β-catenin