[(14)C]Fluciclovine (alias anti-[(14)C]FACBC) uptake and ASCT2 expression in castration-resistant prostate cancer cells.
BACKGROUND
trans-1-Amino-3-[(18)F]fluorocyclobutanecarboxylic acid ([(18)F]fluciclovine, also known as anti-[(18)F]FACBC), is a tracer for positron emission tomography (PET) imaging for detection of tumors such as prostate cancer (PCa). Our previous study showed that ASCT2 (Na(+)-dependent amino acid transporter (AAT)) mediates fluciclovine uptake in androgen-dependent PCa cells; its expression is influenced by androgen, a key hormone in the progression of primary PCa and castration-resistant prostate cancer (CRPC). In this study, we investigated the uptake mechanisms and feasibility of [(18)F]fluciclovine for CRPC in the androgen-dependent PCa cell line LNCaP and LNCaP-derivatives LNCaP-SF and LN-REC4.


METHODS
LNCaP-SF was established after long-term cultivation of LNCaP in steroid-free conditions, and LN-Pre and LN-REC4 were established from LNCaP inoculated in intact and castrated severe combined immunodeficient mice, respectively. Uptake and competitive inhibition experiments were performed with trans-1-amino-3-fluoro[1-(14)C]cyclobutanecarboxylic acid ([(14)C]fluciclovine) to characterize the involvement of AATs in androgen-dependent PCa (LNCaP and LN-Pre) and CRPC-like (LNCaP-SF and LN-REC4) cell lines. AAT expression was analyzed by Western blotting, and [(14)C]fluciclovine uptake in androgen-dependent PCa and CRPC-like cell lines were investigated in the presence or absence of dihydrotestosterone (DHT).


RESULTS
The contribution of Na(+)-dependent AATs to [(14)C]fluciclovine uptake in all cell lines was 88-98%, and [(14)C]fluciclovine uptake was strongly inhibited by L-glutamine and L-serine, the substrates for Na(+)-dependent alanine-serine-cysteine (system ASC) AATs, in the presence of Na(+). DHT enhanced ASCT2 expression in LNCaP, LN-Pre, and LN-REC4, but not in LNCaP-SF, and the responses of ASCT2 expression to DHT correlated with [(14)C]fluciclovine uptake.


CONCLUSIONS
System ASC, especially ASCT2, could play a major role in [(14)C]fluciclovine uptake into CRPC-like and androgen-dependent PCa cells, suggesting [(18)F]fluciclovine-PET is applicable to the detection of CRPC as well as androgen-dependent PCa.


CONCLUSIONS
[(18)F]fluciclovine-PET may be applied for the detection of CRPC.


CONCLUSIONS
[(18)F]fluciclovine-PET may permit early intervention for CRPC treatment.
Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan; Research Center, Nihon Medi-Physics Co., Ltd., Chiba, Japan.
Masahiro
M
Ono
Research Center, Nihon Medi-Physics Co., Ltd., Chiba, Japan. Electronic address: shuntaro_oka@nmp.co.jp.
Shuntaro
S
Oka
Research Center, Nihon Medi-Physics Co., Ltd., Chiba, Japan.
Hiroyuki
H
Okudaira
Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan.
Takeo
T
Nakanishi
Department of Integrative Cancer Therapy and Urology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
Atsushi
A
Mizokami
Wellness Promotion Science Center, Institute of Medical, Pharmaceutical and Health Science, Kanazawa University, Ishikawa, Japan.
Masato
M
Kobayashi
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Science, Emory University, Atlanta, GA, USA.
David M
DM
Schuster
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Science, Emory University, Atlanta, GA, USA.
Mark M
MM
Goodman
Research Center, Nihon Medi-Physics Co., Ltd., Chiba, Japan; Current Address: Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
Yoshifumi
Y
Shirakami
Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.
Keiichi
K
Kawai
D026962:Amino Acid Transport System ASC / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002264:Carboxylic Acids / Q000378:metabolism*; D045744:Cell Line, Tumor; D003503:Cyclobutanes / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D005240:Feasibility Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D015778:Minor Histocompatibility Antigens; D064129:Prostatic Neoplasms, Castration-Resistant / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*
D026962:Amino Acid Transport System ASC; D000728:Androgens; D002264:Carboxylic Acids; D003503:Cyclobutanes; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human; D013196:Dihydrotestosterone; C117460:fluciclovine F-18
ASCT2; Anti-FACBC; CRPC; Fluciclovine; Positron emission tomography; Prostate cancer