Journal
GASTRIC CANCER
Volume 17, Issue 3, Pages 423-430Publisher
SPRINGER
DOI: 10.1007/s10120-013-0314-2
Keywords
FOXO1; Gastric cancer; Cisplatin resistance; PI3K/Akt
Categories
Funding
- SNUH Research Fund [04-2013-0570]
- National Research Foundation of Korea (NRF) Grant - Korean Government [2010-0024702]
- National Research Foundation of Korea [2010-0024702] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ask authors/readers for more resources
Cisplatin (CDDP) is one of the most important chemotherapeutic agents in the treatment of advanced gastric cancer, but its efficacy is limited by CDDP resistance. Because the transcription factor FOXO1 is related to chemoresistance in various cancer cells, we investigated the function of FOXO1 in CDDP resistance in human gastric cancer cells. Human gastric cancer cell lines MKN45 and SNU-601 were used. FOXO1 activation was modulated by transfection of FOXO1 AAA mutant gene or FOXO1 shRNA. The effects of FOXO1 on cell growth and CDDP cytotoxicity were assessed by crystal violet assay. Protein expressions of FOXO1, p110 alpha, pAkt, and Akt were analyzed by Western blotting, and FOXO1 mRNA expression was evaluated by semiquantitative reverse transcription-polymerase chain reaction. FOXO1 activity was determined by luciferase reporter assay, and cell apoptosis was assessed by DAPI staining and Western blotting for PARP cleavage. Cisplatin treatment induced FOXO1 expression and activation in both gastric cancer cell lines. FOXO1 overexpression increased the CDDP resistance without changes in cell growth, whereas FOXO1 silencing enhanced CDDP cytotoxicity along with apoptotic characteristics. Both constitutive and CDDP-induced FOXO1 activations were accompanied by an increase in p110 alpha and pAkt expression. Furthermore, Akt inhibition by LY294002 treatment restored the CDDP cytotoxicity that was suppressed by FOXO1 overexpression. FOXO1 inhibits CDDP-induced apoptosis in gastric cancer cells via activating PI3K/Akt pathway. Thus, FOXO1 may be an useful pharmacological indicator to predict CDDP efficacy in gastric cancer treatment.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available