Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.
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.
Dayon
Audrey
A
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
Brizuela
Leyre
L
Martin
Claire
C
Mazerolles
Catherine
C
Pirot
Nelly
N
Doumerc
Nicolas
N
Nogueira
Leonor
L
Golzio
Muriel
M
Teissié
Justin
J
Serre
Guy
G
Rischmann
Pascal
P
Malavaud
Bernard
B
Cuvillier
Olivier
O
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
D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D008055:Lipids; D009570:Nitriles; D017853:Phosphotransferases (Alcohol Group Acceptor); D014105:Tosyl Compounds; D000099157:Sphingosine Kinase; C053541:bicalutamide