Adeno‐associated virus–delivered short hairpin‐structured RNA for androgen receptor gene silencing induces tumor eradication of prostate cancer xenografts in nude mice: A preclinical study

• Published in: International journal of cancer Vol. 126; no. 3; pp. 764 - 774
• Main Authors: Sun, Aijing, Tang, Jianxi, Terranova, Paul F., Zhang, Xiaoming, Thrasher, James Brantley, Li, Benyi
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2010
• Subjects: Adeno-associated virus; Adenocarcinoma - surgery; Adenocarcinoma - therapy; androgen receptor; Androgen Receptor Antagonists; Androgen receptors; Animals; Apoptosis; Cell death; Cell Line, Tumor - transplantation; Cell survival; Combined Modality Therapy; Data processing; Dependovirus - genetics; Expression vectors; Gene Silencing; Gene therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Genetic Vectors - therapeutic use; Humans; Injections, Intralesional; Male; Mice; Mice, Nude; nude mice xenograft; Orchiectomy; Prostate cancer; Prostatic Neoplasms - surgery; Prostatic Neoplasms - therapy; Receptors, Androgen - genetics; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use; short‐hairpin RNA; siRNA; Tumors; Veins; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24778

The androgen receptor (AR) is the most critical factor in prostate cancer progression. We previously demonstrated that silencing the AR using 2 unique small interfering RNAs (no. 8 and no. 31 AR siRNA) induces apoptotic cell death in AR‐positive prostate cancer cells. To develop this AR siRNA technique into a therapy for prostate cancers, we generated an adeno‐associated virus (AAV) vector to stably express a short hairpin‐structured RNA (shRNA) against the AR gene in vivo. In addition to the no. 8 AR shRNA (ARHP8), we also screened a group of AR shRNAs with different sequences and identified a less effective AR shRNA (ARHP4) that was used as an shRNA control. An empty AAV vector (AAV‐GFP) was used as a negative control. Intratumoral injection of AAV‐ARHP8 viruses significantly suppressed tumor growth of xenografts derived from either androgen‐responsive or castration‐resistant prostate cancer cells. Most interestingly, systemic delivery of the AAV‐ARHP8 but not AAV‐ARHP4 or AAV‐GFP viruses via tail vein injection eliminated xenografts within 10 days. Further analysis revealed that AAV‐ARHP8 viruses dramatically reduced the expression of AR‐regulated cellular survival genes and caused a dramatic apoptotic response. Taken together, our data strongly suggest that AAV‐ARHP8 viruses induced a strong AR gene silencing in vivo and that systemic delivery of ARHP8 siRNA via an AAV vector or any other means might be considered as novel gene therapy for prostate cancers.