title: Inhibition of Tcf-4 induces apoptosis and enhances chemosensitivity of colon cancer cells.
abstract: Aberrant activation of β-catenin/Tcf-4 signaling has been implicated in human carcinogenesis, including colorectal cancer. In this study, we compared the effects of Tcf-4 knockdown with β-catenin knockdown on cell proliferation, apoptosis, and chemosensitivity in SW480 and HCT116 colon cancer cells using adenoviral vector-mediated short hairpin RNA (shRNA). Our results show that, compared to β-catenin knockdown, Tcf-4 knockdown more effectively inhibited colony formation, induced apoptosis, and increased 5-FU and oxaliplatin-mediated cytotoxicity in colon cancer cells. We further investigated the mechanisms involved in the different efficacies observed with β-catenin and Tcf-4 knockdown in colon cancer cells. FOXO4 is a member of the subfamily of mammalian FOXO forkhead transcription factors and plays a major role in controlling cellular proliferation, apoptosis, and DNA repair. Our data showed that the protein level of FOXO4 did not change after treatment with both β-catenin and Tcf-4 shRNA. However, β-catenin shRNA was found to increase the accumulation of phosphorylated FOXO4 S193 and decrease the expression of FOXO target genes p27Kip1 and MnSOD, whereas Tcf-4 shRNA showed the opposite effect. Therefore, compared to β-catenin knockdown, Tcf-4 knockdown shows better efficacy for inhibiting proliferation and inducing apoptosis of colorectal cancer cells, which may be related to increased FOXO4 transcriptional activity. These results suggest that Tcf-4 is an attractive potential therapeutic target for colorectal cancer therapy.
authors.affiliation: Children's Hospital, Chongqing Medical University, Chongqing, China. jiangxie_cd@hotmail.com
authors.forename: Jiang
authors.initials: J
authors.lastname: Xie
authors.forename: De-Bing
authors.initials: DB
authors.lastname: Xiang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Cong
authors.initials: C
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Xiong
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Li
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers; D005472:Fluorouracil / Q000494:pharmacology; D051858:Forkhead Transcription Factors; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D045325:HCT116 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D017931:DNA Primers; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D009944:Organoplatinum Compounds; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D000077150:Oxaliplatin; D005472:Fluorouracil