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Inhibition of PI3K/Akt partially leads to the inhibition of PrP C ‐induced drug resistance in gastric cancer cells
Author(s) -
Liang Jie,
Ge Fulin,
Guo Changcun,
Luo Guanhong,
Wang Xin,
Han Guohong,
Zhang Dexin,
Wang Jianhong,
Li Kai,
Pan Yanglin,
Yao Liping,
Yin Zhanxin,
Guo Xuegang,
Wu Kaichun,
Ding Jie,
Fan Daiming
Publication year - 2009
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2008.06816.x
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , downregulation and upregulation , cancer research , small interfering rna , cancer cell , ly294002 , biology , multiple drug resistance , chemistry , cancer , cell culture , microbiology and biotechnology , phosphorylation , transfection , signal transduction , drug resistance , biochemistry , gene , genetics
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.