The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-11-08

AUTHORS

Jinju Park, Young San Ko, Jiyeon Yoon, Min A. Kim, Jong-Wan Park, Woo Ho Kim, Youngsun Choi, Ji Hun Kim, Younghee Cheon, Byung Lan Lee

ABSTRACT

BackgroundCisplatin (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.MethodsHuman 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, p110α, 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.ResultsCisplatin 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 p110α and pAkt expression. Furthermore, Akt inhibition by LY294002 treatment restored the CDDP cytotoxicity that was suppressed by FOXO1 overexpression.ConclusionFOXO1 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. More... »

PAGES

423-430

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10120-013-0314-2

DOI

http://dx.doi.org/10.1007/s10120-013-0314-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1023357321

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24202965


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82 cisplatin resistance
83 cleavage
84 crystal violet
85 cytotoxicity
86 effect
87 effect of FoxO1
88 efficacy
89 enhanced CDDP cytotoxicity
90 expression
91 factor FOXO1
92 forkhead transcription factor FOXO1
93 function
94 function of FOXO1
95 gastric cancer
96 gastric cancer cell line MKN45
97 gastric cancer cell lines
98 gastric cancer cells
99 gastric cancer treatment
100 genes
101 growth
102 human gastric cancer cells
103 important chemotherapeutic agent
104 increase
105 indicators
106 inhibition
107 lines
108 lines MKN45
109 luciferase reporter
110 mRNA expression
111 mutant gene
112 overexpression
113 p110α
114 pAkt
115 pAkt expression
116 pathway
117 pharmacological indicator
118 phosphoinositide
119 protein expression
120 reaction
121 reporter
122 resistance
123 reverse transcription-polymerase chain reaction
124 semiquantitative reverse transcription-polymerase chain reaction
125 shRNA
126 staining
127 transcription factor FOXO1
128 transcription-polymerase chain reaction
129 transfection
130 treatment
131 useful pharmacological indicator
132 violet
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