title: Serotonin promotes the proliferation of serum-deprived hepatocellular carcinoma cells via upregulation of FOXO3a.
abstract: BACKGROUND
  Peripheral serotonin is involved in tumorigenesis and induces a pro-proliferative effect in hepatocellular carcinoma (HCC) cells; however, the intracellular mechanisms by which serotonin exerts a mitogenic effect remain unclear. In this research, we examined whether FOXO3a, a transcription factor at the interface of crucial cellular processes, plays a role downstream of serotonin in HCC cells.
  
  
  RESULTS
  The cell viability and expression of FOXO3a was assessed in three HCC cell lines (Huh7, HepG2 and Hep3B) during serum deprivation in the presence or absence of serotonin. Serum free media significantly inhibited HCC proliferation and led to reduced expression and nuclear accumulation of FOXO3a. Knockdown of FOXO3a enhanced the ability of serum deprivation to inhibit HCC cells proliferation. And overexpression of non-phosphorylated FOXO3a in HCC cells reversed serum-deprivation-induced growth inhibition. Serotonin reversed the serum-deprivation-induced inhibition of cell proliferation and upregulated FOXO3a in Huh7 cells; however, serotonin had no effect on the proliferation of serum-deprived HepG2 or Hep3B cells. In addition to proliferation, serotonin also induced phosphorylation of AKT and FOXO3a in serum-deprived Huh7 cells but not in HepG2 and Hep3B cells. However, the phosphorylation of FOXO3a induced by serotonin did not export FOXO3a from nucleus to cytoplasm in serum-deprived Huh7 cells. Consequently, we demonstrated that serotonin promoted the proliferation of Huh7 cells by increasing the expression of FOXO3a. We also provide preliminary evidence that different expression levels of the 5-HT2B receptor (5-HT2BR) may contribute to the distinct effects of serotonin in different serum-deprived HCC cells.
  
  
  CONCLUSIONS
  This study demonstrates that FOXO3a functions as a growth factor in serum-deprived HCC cells and serotonin promotes the proliferation of serum-deprived HCC cells via upregulation of FOXO3a, in the presence of sufficient levels of the serotonin receptor 5-HT2BR. Drugs targeting the serotonin-5-HT2BR-FOXO3a pathway may provide a novel target for anticancer therapy.
authors: Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, China.
authors: Chao
authors: C
authors: Liang
authors: Wei
authors: W
authors: Chen
authors: Xiao
authors: X
authors: Zhi
authors: Tao
authors: T
authors: Ma
authors: Xuefeng
authors: X
authors: Xia
authors: Hao
authors: H
authors: Liu
authors: Qi
authors: Q
authors: Zhang
authors: Qida
authors: Q
authors: Hu
authors: Yun
authors: Y
authors: Zhang
authors: Xueli
authors: X
authors: Bai
authors: Tingbo
authors: T
authors: Liang
mesh_terms: D006528:Carcinoma, Hepatocellular; D049109:Cell Proliferation; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D016895:Culture Media, Serum-Free; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D044403:Receptor, Serotonin, 5-HT2B; D012701:Serotonin; D051057:Proto-Oncogene Proteins c-akt