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.
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.
Sun
Aijing
A
Department of Pathology, Shaoxing People's Hospital and the First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China.
Tang
Jianxi
J
Terranova
Paul F
PF
Zhang
Xiaoming
X
Thrasher
James Brantley
JB
Li
Benyi
B
D000230:Adenocarcinoma / Q000601:surgery / Q000628:therapy*; D059002:Androgen Receptor Antagonists; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor / Q000637:transplantation; D003131:Combined Modality Therapy; D000229:Dependovirus / Q000235:genetics*; D020868:Gene Silencing; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000601:surgery / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D011944:Receptors, Androgen / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D034741:RNA, Small Interfering; D011944:Receptors, Androgen