title: Knockdown of RON inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells.
abstract: OBJECTIVE
  Altered Recepteur d'Origine nantais (RON) expression transduces signals inducting invasive growth phenotype that includes cell proliferation, migration, matrix invasion, and protection of apoptosis in human cancer cells. The aims of the current study were to evaluate whether RON affects tumor cell behavior and cellular signaling pathways including activator protein-1 (AP-1) and Akt/forkhead box O (FoxO) in human colorectal cancer cells.
  
  
  METHODS
  To study the biological role of RON on tumor cell behavior and cellular signaling pathways in human colorectal cancer, we used small interfering RNA (siRNA) to knockdown RON gene expression in human colorectal cancer cell line, DKO-1.
  
  
  RESULTS
  Knockdown of RON diminished migration, invasion, and proliferation of human colorectal cancer cells. Knockdown of RON decreased AP-1 transcriptional activity and expression of AP-1 target genes. Knockdown of RON activated cleaved caspase-3, -7, -9, and PARP, and down-regulated the expression of Mcl-1, survivin and XIAP, leading to induction of apoptosis. Knockdown of RON induced cell cycle arrest in the G2/M phase of cancer cells by an increase of p27 and a decrease of cyclin D3. Knockdown of RON inhibited the phosphorylation of Akt/FoxO signaling proteins such as Ser473 and Thr308 of Akt and FoxO1/3a.
  
  
  CONCLUSIONS
  These results indicate that knockdown of RON inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells.
authors: Department of Internal Medicine, Chonnam National University Medical School, 8 Hak-Dong, Dong-ku, Gwangju, 501-757, Korea.
authors: Cho-Yun
authors: CY
authors: Chung
authors: Young-Lan
authors: YL
authors: Park
authors: Young-A
authors: YA
authors: Song
authors: Eun
authors: E
authors: Myung
authors: Kyu-Yeol
authors: KY
authors: Kim
authors: Gi-Hoon
authors: GH
authors: Lee
authors: Ho-Seok
authors: HS
authors: Ki
authors: Kang-Jin
authors: KJ
authors: Park
authors: Sung-Bum
authors: SB
authors: Cho
authors: Wan-Sik
authors: WS
authors: Lee
authors: Young-Do
authors: YD
authors: Jung
authors: Kyung-Keun
authors: KK
authors: Kim
authors: Young-Eun
authors: YE
authors: Joo
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D015179:Colorectal Neoplasms; D015536:Down-Regulation / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases