Cancer cells require massive amounts of amino acids for survival. L-type amino acid transporter 1 (LAT1) transports essential amino acids, including leucine, which trigger the downstream m-TOR pathway.
The association between androgen receptor (AR) and LAT1 and the association between LAT1 expression and acquisition of castration resistance were examined.
Western blotting and real-time polymerase chain reaction were used to study protein and mRNA expressions. SiRNA was used to knockdown target genes. 92 prostate biopsies specimen of patients who underwent androgen deprivation therapy (ADT) were used for immunohistochemical analyses. Cox hazard proportional models and the Kaplan-Meier method were used for statistical analyses.
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. SiRNA of AR or blocking of AR through bicalutamide (10μΜ) or MDV3100 (10μΜ) significantly increased LAT1 expression (P<0. 01). Treatment with DHT (0. 1-10 nM) reduced LAT1 expression in a dose-dependent manner (P<0. 01). Bicalutamide/MDV3100 plus SiLAT1synergistically suppressed prostate cancer cell proliferation compared to single inhibition of AR or LAT1 (P<0. 01). The high LAT1 expression correlated with significantly shorter PSA recurrence free survival in patients receiving ADT (P<0. 0001). LAT1 expression (HR 3. 56, P = 0. 0133) was an independent predictor of castration resistance on multivariate analysis.
The current data may provide a novel mechanism to acquire castration resistance through activation of amino acid transporter LAT1.
The Journal of urology. 2015 Dec 09 [Epub ahead of print]
Minhui Xu, Shinichi Sakamoto, Jun Matsushima, Toru Kimura, Takeshi Ueda, Atsushi Mizokami, Yoshikatsu Kanai, Tomohiko Ichikawa
Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan. , Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan. Departments of Diagnostic Pathology, Chiba University Graduate School of Medicine, Chiba, Japan. , Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan. , Prostate Center and Division of Urology, Chiba Cancer Center, Chiba, Japan. , Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan. , Division of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan. , Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.