[14C]Fluciclovine (alias anti-[14C]FACBC) uptake and ASCT2 expression in castration-resistant prostate cancer cells

• DOI: 10.1016/j.nucmedbio.2015.07.005
• Publication Date: 2015-07-15T19:18:26Z
• Authors: Masahiro Ono; Shuntaro Oka; Hiroyuki Okudaira; Takeo Nakanishi; Atsushi Mizokami; Masato Kobayashi; David M. Schuster; Mark M. Goodman; Yoshifumi Shirakami; Keiichi Kawai
• Keywords: Amino Acid Transport System ASC; Male; Carboxylic Acids; Biological Transport; Dihydrotestosterone; Binding, Competitive; 3. Good health; Gene Expression Regulation, Neoplastic; Minor Histocompatibility Antigens; Mice; Prostatic Neoplasms, Castration-Resistant; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Androgens; Animals; Feasibility Studies; Humans; Cyclobutanes

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.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).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.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.[(18)F]fluciclovine-PET may be applied for the detection of CRPC.[(18)F]fluciclovine-PET may permit early intervention for CRPC treatment.