title: A peptide derived from phage display library exhibits anti-tumor activity by targeting GRP78 in gastric cancer multidrug resistance cells.
abstract: Multidrug resistance (MDR) remains a significant challenge to the clinical treatment of gastric cancer (GC). In the present study, using a phage display approach combined with MTT assays, we screened a specific peptide GMBP1 (Gastric cancer MDR cell-specific binding peptide), ETAPLSTMLSPY, which could bind to the surface of GC MDR cells specifically and reverse their MDR phenotypes. Immunocytochemical staining showed that the potential receptor of GMBP1 was located at the membrane and cytoplasm of MDR cells. In vitro and in vivo drug sensitivity assays, FACS analysis and Western blotting confirmed that GMBP1 was able to re-sensitize MDR cells to chemical drugs. Western blotting and proteomic approaches were used to screen the receptor of GMBP1, and GRP78, a MDR-related protein, was identified as a receptor of GMBP1. This result was further supported by immunofluoresence microscopy and Western blot. Additionally, Western blotting demonstrated that pre-incubation of GMBP1 in MDR cells greatly diminished MDR1, Bcl-2 and GRP78 expression but increased the expression of Bax, whereas downregulation of GRP78, function as a receptor and directly target for GMBP1, only inhibited MDR1 expression. Our findings suggest that GMBP1 could re-sensitize GC MDR cells to a variety of chemotherapeutic agents and this role might be mediated partly through down-regulating GRP78 expression and then inhibiting MDR1 expression. These findings indicate that peptide GMBP1 likely recognizes a novel GRP78 receptor and mediates cellular activities associated with the MDR phenotype, which provides new insight into research on the management of MDR in gastric cancer cells.
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jianqin
authors.initials: J
authors.lastname: Kang
authors.forename: Guohong
authors.initials: G
authors.lastname: Zhao
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.forename: Shanhong
authors.initials: S
authors.lastname: Tang
authors.forename: Guanghui
authors.initials: G
authors.lastname: Xu
authors.forename: Sijun
authors.initials: S
authors.lastname: Hu
authors.forename: Qian
authors.initials: Q
authors.lastname: Bi
authors.forename: Changcun
authors.initials: C
authors.lastname: Guo
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Shuang
authors.initials: S
authors.lastname: Han
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.forename: Biaoluo
authors.initials: B
authors.lastname: Wang
authors.forename: Shuhui
authors.initials: S
authors.lastname: Liang
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019151:Peptide Library; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000604907:GMBP1 peptide; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D009842:Oligopeptides; D019151:Peptide Library; D011956:Receptors, Cell Surface
keywords: GRP78; Gastric cancer; MDR; Peptide; Phage display peptide library