title: Inhibition of PI3K/Akt partially leads to the inhibition of PrP(C)-induced drug resistance in gastric cancer cells.
abstract: Cellular prion protein (PrP(C)), a glycosyl-phosphatidylinositol-anchored membrane protein with unclear physiological function, was previous found to be upregulated in adriamycin (ADR)-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Overexpression of PrP(C) in gastric cancer has certain effects on drug accumulation through upregulation of P-glycoprotein (P-gp), which is suggested to play an important role in determining the sensitivity of tumor cells to chemotherapy and is linked to activation of the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway. In the present study, we further investigate the role of the PI3K/Akt pathway in PrP(C)-induced multidrug-resistance (MDR) in gastric cancer. Immunohistochemistry and confocal microscope detection suggest a positive correlation between PrP(C) and phosphorylated Akt (p-Akt) expression in gastric cancer. Using established stable PrP(C) transfectant cell lines, we demonstrated that the level of p-Akt was increased in PrP(C)-transfected cells. Inhibition of PrP(C) expression by RNA interference resulted in decreased p-Akt expression. Inhibition of the PI3K/Akt pathway by one of its specific inhibitors, LY294002, or by Akt small interfering RNA (siRNA) resulted in decreased multidrug resistance of SGC7901 cells, partly through downregulation of P-gp induced by PrP(C). Taken together, our results suggest that PrP(C)-induced MDR in gastric cancer is associated with activation of the PI3K/Akt pathway. Inhibition of PI3K/Akt by LY2940002 or Akt siRNA leads to inhibition of PrP(C)-induced drug resistance and P-gp upregulation in gastric cancer cells, indicating a possible novel mechanism by which PrP(C) regulates gastric cancer cell survival.
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.forename: Fulin
authors.initials: F
authors.lastname: Ge
authors.forename: Changcun
authors.initials: C
authors.lastname: Guo
authors.forename: Guanhong
authors.initials: G
authors.lastname: Luo
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Guohong
authors.initials: G
authors.lastname: Han
authors.forename: Dexin
authors.initials: D
authors.lastname: Zhang
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Yanglin
authors.initials: Y
authors.lastname: Pan
authors.forename: Liping
authors.initials: L
authors.lastname: Yao
authors.forename: Zhanxin
authors.initials: Z
authors.lastname: Yin
authors.forename: Xuegang
authors.initials: X
authors.lastname: Guo
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011328:Prions; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt