title: Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.
abstract: BACKGROUND
  Sphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival.
  
  
  RESULTS
  Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity.
  
  
  CONCLUSIONS
  We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer.
authors: CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
authors: Audrey
authors: A
authors: Dayon
authors: Leyre
authors: L
authors: Brizuela
authors: Claire
authors: C
authors: Martin
authors: Catherine
authors: C
authors: Mazerolles
authors: Nelly
authors: N
authors: Pirot
authors: Nicolas
authors: N
authors: Doumerc
authors: Leonor
authors: L
authors: Nogueira
authors: Muriel
authors: M
authors: Golzio
authors: Justin
authors: J
authors: Teissié
authors: Guy
authors: G
authors: Serre
authors: Pascal
authors: P
authors: Rischmann
authors: Bernard
authors: B
authors: Malavaud
authors: Olivier
authors: O
authors: Cuvillier
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D014105:Tosyl Compounds / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D008055:Lipids; D009570:Nitriles; D017853:Phosphotransferases (Alcohol Group Acceptor); D014105:Tosyl Compounds; D000099157:Sphingosine Kinase; C053541:bicalutamide