Up-Regulation of LAT1 during Antiandrogen Therapy Contributes to Progression in Prostate Cancer Cells

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• 作者：Minhui Xu^a ; ^&lowast ; ; Shinichi Sakamoto^a ; ^&lowast ; ; ^{rbatbat1@yahoo.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Jun Matsushima^b ; Toru Kimura^d ; Takeshi Ueda^c ; Atsushi Mizokami^e ; Yoshikatsu Kanai^f ; Tomohiko Ichikawa^a
• 关键词：prostatic neoplasms ; castration ; androgen antagonists ; treatment failure ; large neutral amino acid-transporter 1
• 刊名：The Journal of Urology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：195
• 期：5
• 页码：1588-1597
• 全文大小：2533 K

文摘

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

15">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.