title: Prostate cancer-specific and potent antitumor effect of a DD3-controlled oncolytic virus harboring the PTEN gene.
abstract: Prostate cancer is a major health problem for men in Western societies. Here we report a Prostate Cancer-Specific Targeting Gene-Viro-Therapy (CTGVT-PCa), in which PTEN was inserted into a DD3-controlled oncolytic viral vector (OV) to form Ad.DD3.E1A.E1B(Δ55)-(PTEN) or, briefly, Ad.DD3.D55-PTEN. The woodchuck post-transcriptional element (WPRE) was also introduced at the downstream of the E1A coding sequence, resulting in much higher expression of the E1A gene. DD3 is one of the most prostate cancer-specific genes and has been used as a clinical bio-diagnostic marker. PTEN is frequently inactivated in primary prostate cancers, which is crucial for prostate cancer progression. Therefore, the Ad.DD3.D55-PTEN has prostate cancer specific and potent antitumor effect. The tumor growth rate was almost completely inhibited with the final tumor volume after Ad.DD3.D55-PTEN treatment less than the initial volume at the beginning of Ad.DD3.D55-PTEN treatment, which shows the powerful antitumor effect of Ad.DD3.D55-PTEN on prostate cancer tumor growth. The CTGVT-PCa construct reported here killed all of the prostate cancer cell lines tested, such as DU145, 22RV1 and CL1, but had a reduced or no killing effect on all the non-prostate cancer cell lines tested. The mechanism of action of Ad.DD3.D55-PTEN was due to the induction of apoptosis, as detected by TUNEL assays and flow cytometry. The apoptosis was mediated by mitochondria-dependent and -independent pathways, as determined by caspase assays and mitochondrial membrane potential.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Ding
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.forename: Hai-neng
authors.initials: HN
authors.lastname: Xu
authors.forename: Jun-kai
authors.initials: JK
authors.lastname: Fan
authors.forename: Hong-ling
authors.initials: HL
authors.lastname: Huang
authors.forename: Dong-qin
authors.initials: DQ
authors.lastname: Yang
authors.forename: Yu-hua
authors.initials: YH
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Runsheng
authors.initials: R
authors.lastname: Li
authors.forename: Xin-yuan
authors.initials: XY
authors.lastname: Liu
mesh_terms: D017500:Adenovirus E1A Proteins; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy*
chemical_list: D017500:Adenovirus E1A Proteins; D000951:Antigens, Neoplasm; C479341:prostate cancer antigen 3, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human