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Arachidonic acid activation of intratumoral steroid synthesis during prostate cancer progression to castration resistance
Author(s) -
Locke Jennifer A.,
Guns Emma S. Tomlinson,
Lehman Melanie L.,
Ettinger Susan,
Zoubeidi Amina,
Lubik Amy,
Margiotti Katia,
Fazli Ladan,
Adomat Hans,
Wasan Kishor M.,
Gleave Martin E.,
Nelson Colleen C.
Publication year - 2009
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21057
Subject(s) - arachidonic acid , lncap , endocrinology , androgen , prostate cancer , androgen receptor , medicine , steroidogenic acute regulatory protein , cancer research , biology , chemistry , hormone , biochemistry , cancer , gene expression , gene , enzyme
BACKGROUND De novo androgen synthesis and subsequent androgen receptor (AR) activation has recently been shown to contribute to castration‐resistant prostate cancer (CRPC) progression. Herein we provide evidence that fatty acids (FA) can trigger androgen synthesis within steroid starved prostate cancer (CaP) tumor cells. METHODS Tumoral FA and steroid levels were assessed by GC–MS and LC–MS, respectively. Profiles of genes and proteins involved in FA activation of steroidogenesis were assessed by fluorescence microscopy, immunohistochemistry, microarray expression profiling and Western blot analysis. RESULTS In human CaP tissues the levels of proteins responsible for FA activation of steroid synthesis were observed to be altered during progression to CRPC. Further investigating this mechanism in LNCaP cells, we demonstrate that specific FA, arachidonic acid, is synthesized in an androgen‐dependent and AR‐mediated manner. Arachidonic acid is known to induce steroidogenic acute regulatory protein (StAR) in steroidogenic cells. When bound to hormone sensitive lipase (HSL), StAR shuttles free cholesterol into the mitochondria for downstream conversion into androgens. We show that arachidonic acid induces androgen production in steroid starved LNCaP cells coincidently in the same conditions that HSL and StAR are predominantly localized in the mitochondria. Furthermore, their activities are verified by a functional increase in mitochondrial uptake of cholesterol in this steroid starved environment. CONCLUSIONS We propose that this characterized arachidonic acid induced steroidogenesis mechanism significantly contributes to the activation of AR in CRPC progression and therefore recommend that fatty acid pathways be targeted therapeutically in progressing CaP. Prostate 70: 239–251, 2010. © 2009 Wiley‐Liss, Inc.