Open AccessThe central role of Sphingosine kinase 1 in the development of neuroendocrine prostate cancer (NEPC): A new targeted therapy of NEPC
Author(s) -
Lee ChengFan,
Chen YuAn,
Hernandez Elizabeth,
Pong ReyChen,
Ma Shihong,
Hofstad Mia,
Kapur Payal,
Zhau Haiyen,
Chung Leland WK,
Lai ChihHo,
Lin Ho,
Lee MingShyue,
Raj Ganesh V,
Hsieh JerTsong
Publication year - 2022
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.695
Subject(s) - prostate cancer , cancer research , sphingosine kinase 1 , biology , transcription factor , androgen receptor , sphingosine , cancer , medicine , gene , sphingosine 1 phosphate , receptor , genetics
Background Neuroendocrine prostate cancer (NEPC) is often diagnosed as a sub‐type from the castration‐resistant prostate cancer (CRPC) recurred from the second generation of anti‐androgen treatment and is a rapidly progressive fatal disease. The molecular mechanisms underlying the trans‐differentiation from CRPC to NEPC are not fully characterized, which hampers the development of effective targeted therapy. Methods Bioinformatic analyses were conducted to determine the clinical correlation of sphingosine kinase 1 (SphK1) in CRPC progression. To investigate the transcriptional regulation SphK1 and neuroendocrine (NE) transcription factor genes, both chromosome immunoprecipitation and luciferase reporter gene assays were performed. To demonstrate the role of SphK1 in NEPC development, neurosphere assay was carried out along with several biomarkers determined by quantitative PCR and western blot. Furthermore, in vivo NEPC xenograft models and patient‐derived xenograft (PDX) model were employed to determine the effect of SphK1 inhibitors and target validation. Results Significant prevalence of SphK1 in NEPC development is observed from clinical datasets. SphK1 is transcriptionally repressed by androgen receptor‐RE1‐silencing transcription factor (REST) complex. Furthermore, sphingosine 1‐phosphate produced by SphK1 can modulate REST protein turnover via MAPK signaling pathway. Also, decreased REST protein levels enhance the expression of NE markers in CRPC, enabling the transition to NEPC. Finally, specific SphK1 inhibitors can effectively inhibit the growth of NEPC tumors and block the REST protein degradation in PDX. Conclusions SphK1 plays a central role in NEPC development, which offers a new target for this lethal cancer using clinically approved SphK1 inhibitors.