Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase.
Alteration in genes which takes place during malignant conversion and progression could be potential targets for gene therapy. We previously identified REIC/Dkk-3 as a gene whose expression is reduced in many human cancers. Here, we showed that expression of REIC/Dkk-3 was consistently reduced in human prostate cancer tissues in a stage-dependent manner. Forced expression of REIC/Dkk-3 induced apoptosis in human prostate cancer cell lines lacking endogenous REIC/Dkk-3 expression but not in REIC/Dkk-3-proficient normal prostate epithelial and stromal cells. The apoptosis involved c-Jun-NH2-kinase activation, mitochondrial translocation of Bax, and reduction of Bcl-2. A single injection of an adenovirus vector carrying REIC/Dkk-3 showed a dramatic antitumor effect on a xenotransplanted human prostate cancer. Thus, REIC/Dkk-3 could be a novel target for gene-based therapy of prostate cancer.
Abarzua
Fernando
F
Departments of Cell Biology and Urology, Okayama University Graduate School of Medicine and Dentistry, Okayama.
Sakaguchi
Masakiyo
M
Takaishi
Mikiro
M
Nasu
Yasutomo
Y
Kurose
Kyouhei
K
Ebara
Shin
S
Miyazaki
Masahiro
M
Namba
Masayoshi
M
Kumon
Hiromi
H
Huh
Nam-ho
NH
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D018925:Chemokines; D004789:Enzyme Activation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D048031:JNK Mitogen-Activated Protein Kinases