RRC ID 61099
著者 Xu M, Sakamoto S, Matsushima J, Kimura T, Ueda T, Mizokami A, Kanai Y, Ichikawa T.
タイトル Up-Regulation of LAT1 during Antiandrogen Therapy Contributes to Progression in Prostate Cancer Cells.
ジャーナル J Urol
Abstract PURPOSE:Cancer cells require massive amounts of amino acids for survival. LAT1 (L-type amino acid transporter 1) transports essential amino acids, including leucine, which trigger the downstream mTOR (mammalian target of rapamycin) pathway. We examined the association between androgen receptor and LAT1, and the association between LAT1 expression and the acquisition of castration resistance.
MATERIALS AND METHODS:Western blot and real-time polymerase chain reaction were performed to study protein and mRNA expression. siRNA was used to knock down target genes. A total of 92 prostate biopsy specimens of patients who underwent androgen deprivation therapy were used for immunohistochemical analyses. Cox hazard proportional models and the Kaplan-Meier method were used for statistical analyses.
RESULTS:LAT1 was highly expressed in hormone resistant prostate cancer cell lines. Knockdown of LAT1 in LNCaP and C4-2 cells significantly suppressed cell proliferation, migration and invasion. Androgen receptor siRNA or androgen receptor blocking through bicalutamide (10 μM) or MDV3100 (10 μM) significantly increased LAT1 expression (p <0.01). Treatment with dihydrotestosterone (0.1 to 10 nM) reduced LAT1 expression in a dose dependent manner (p <0.01). Bicalutamide/MDV3100 plus siLAT1 synergistically suppressed prostate cancer cell proliferation compared to single inhibition by androgen receptor or LAT1 (p <0.01). High LAT1 expression correlated with significantly shorter prostate specific antigen recurrence-free survival in patients receiving androgen deprivation therapy (p <0.0001). LAT1 expression was an independent predictor of castration resistance on multivariate analysis (HR 3.56, p = 0.0133).
CONCLUSIONS:The current data may indicate a novel mechanism to acquire castration resistance through activation of the amino acid transporter LAT1.
巻・号 195(5)
ページ 1588-1597
公開日 2016-5-1
DOI 10.1016/j.juro.2015.11.071
PII S0022-5347(15)05395-1
PMID 26682754
MeSH Aged Androgen Antagonists / therapeutic use Anilides / therapeutic use* Biopsy Blotting, Western Cell Line, Tumor Cell Proliferation / drug effects Disease Progression Gene Expression Regulation, Neoplastic / drug effects* Humans Large Neutral Amino Acid-Transporter 1 / biosynthesis Large Neutral Amino Acid-Transporter 1 / genetics* Male Nitriles / therapeutic use* Prostate / pathology* Prostatic Neoplasms / drug therapy Prostatic Neoplasms / genetics* Prostatic Neoplasms / metabolism RNA, Neoplasm / genetics* Real-Time Polymerase Chain Reaction Tosyl Compounds / therapeutic use* Up-Regulation / drug effects*
IF 5.925
リソース情報
ヒト・動物細胞 LNCap.FGC(RCB2144) DU145(RCB2143)