[Indomethacin induces apoptosis through inhibition of survivin regulated by beta-catenin/TCF4 in human colorectal cancer cells].
OBJECTIVE
Although Wnt pathway plays important role in colorectal carcinogenesis, but the mechanism of this pathway in anti-apoptosis is not clear. This study is to investigate the molecular mechanism of Wnt pathway in anti-apoptosis.


METHODS
Survivin promoter region was constructed into luciferase reporter system (pGL3-sur1.8kb). The recombinants pGL3-sur1.8kb were cotransfected with pRL-SV40 into HCT116 cells and the activities were detected with Dual-luciferase reporter assay system. Cell apoptosis was analyzed by flow cytometry. Protein level of survivin and beta-catenin was detected by Western Blot.


RESULTS
Survivin could be up-regulated by beta-catenin and down-regulated by TCF4DeltaN in transcriptional level. beta-catenin/TCF4 dependent apoptosis induced by indomethacin could suppress survivin transcription. Overexpression of survivin could partially recover the beta-catenin/TCF4 dependent apoptosis.


CONCLUSIONS
Down-regulation of survivin affected by beta-catenin/TCF4 pathway plays an important role in apoptosis induced by NSAIDs indomethacin in HCT116 cells. The beta-catenin/TCF4-survivin pathway may be a potential target in treatment of colon cancer.
Zhu
Hong-Xia
HX
Laboratory of Cell and Molecular Biology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, P.R.China. xningzhi@public.bta.net.cn
Zhang
Guo
G
Wang
Yi-Hua
YH
Zhou
Cui-Qi
CQ
Bai
Jin-Feng
JF
Xu
Ning-Zhi
NZ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D000077022:Survivin; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; C107489:BIRC5 protein, human; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D007213:Indomethacin