Arachidonic acid activation of intratumoral steroid synthesis during prostate cancer progression to castration resistance.
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.
Locke
Jennifer A
JA
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Guns
Emma S Tomlinson
ES
Lehman
Melanie L
ML
Ettinger
Susan
S
Zoubeidi
Amina
A
Lubik
Amy
A
Margiotti
Katia
K
Fazli
Ladan
L
Adomat
Hans
H
Wasan
Kishor M
KM
Gleave
Martin E
ME
Nelson
Colleen C
CC
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000493:pharmacokinetics; D018450:Disease Progression; D004351:Drug Resistance; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*; D002787:Sterol Esterase / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D000098682:Steroidogenic Acute Regulatory Protein
D000726:Androgen Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011944:Receptors, Androgen; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; D016718:Arachidonic Acid; D002784:Cholesterol; D002787:Sterol Esterase