Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines

Urol Oncol. Jul-Aug 2011;29(4):436-45. doi: 10.1016/j.urolonc.2009.09.013. Epub 2009 Nov 19.

Abstract

Purpose: This study was conducted to examine the effects of 5-HT on extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt pathways in prostate cancer (PC) cells.

Methods: PC cell lines PC-3, Du145, and LNCaP stimulated with 5-HT in the presence of MEK or PI3K inhibitors and 5-HT receptor subtype 1A antagonist were analyzed by Western blotting and immunofluorescence. The proliferation assay BrdU and Boyden chamber were used to determine proliferation and migration, respectively.

Results: 5-HT dose-dependently induced rapid activation of Erk1/2 in PC-3 and Du145 cells, whereas in LNCaP cells, Erk1/2 phosphorylation was slow and sustained for up to 18 h. Similarly, 5-HT induced phosphorylation of Akt within 1 hour of stimulation, however, Akt phosphorylation was more pronounced in Du145 cells compared with PC-3 or LNCaP cells. The action of 5-HT was inhibited to varying degrees by inhibitors of MAPK and PI3K as well as by a 5-HT receptor subtype 1A antagonist. In addition to proliferation, 5-HT induced migration of PC-3 and Du145 cells, which were alleviated by the aforementioned inhibitors. The effects of 5-HT on LNCaP cells appeared to be related to neuroendocrine-phenotype acquisition and chromogranin A and neuron specific enolase expression.

Conclusions: This study addresses the role of 5-HT in Erk1/2 and Akt activation in PC cells. The data presented here identify 5-HT receptors as a novel target in castration-resistant PC. Furthermore, our observations are in line with previous studies, which point towards neuroendocrine factors facilitating progression and migration of prostatic cancer cells in an androgen-deficient environment. Nonetheless, additional studies are warranted to corroborate the role of 5-HTR antagonists as a potential target for anticancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Butadienes / pharmacology
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Fluorescent Antibody Technique
  • Humans
  • Male
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Morpholines / pharmacology
  • Neurosecretory Systems / pathology
  • Nitriles / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Piperazines / pharmacology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Serotonin / pharmacology*
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Signal Transduction / drug effects*
  • Time Factors

Substances

  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Nitriles
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • U 0126
  • 1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Serotonin
  • Proto-Oncogene Proteins c-akt
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3