An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis.
Overexpression of REIC/Dkk-3 (a tumor suppressor gene) induces cancer cell apoptosis through endoplasmic reticulum (ER) stress. Therefore, the identification of the portion of REIC/Dkk-3 that causes ER stress may be essential for the development of cancer treatment based on REIC/Dkk-3. Here, we made several truncated forms of REIC/Dkk-3 and investigated their therapeutic potentials against prostate cancer. Among three truncated forms, a variant comprising the N-terminal 78 amino acid region of REIC/Dkk-3 ((1-78)REIC/Dkk-3) most strongly induced ER stress and apoptosis in human prostate cancer cells (PC3). For in vivo gene expression, we coupled a biodegradable polymer with naked DNA, which attained robust trans-gene expression in PC3-derived subcutaneous tumor. In therapeutic experiments, we demonstrated that multiple direct injections of polymer-conjugated (1-78)REIC/Dkk-3 plasmid provoke ER stress and significantly reduced the subcutaneous tumor volume compared with the control group. We suggest this non-viral strategy may be an effective alternative to viral gene therapy.
Abarzua
Fernando
F
Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata 2-5-1, Okayama 700-8558, Japan.
Kashiwakura
Yuji
Y
Takaoka
Munenori
M
Watanabe
Masami
M
Ochiai
Kazuhiko
K
Sakaguchi
Masakiyo
M
Iwawaki
Takao
T
Tanimoto
Ryuta
R
Nasu
Yasutomo
Y
Huh
Nam-Ho
NH
Kumon
Hiromi
H
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D018925:Chemokines; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011108:Polymers / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000628:therapy*; D017384:Sequence Deletion; D014162:Transfection / Q000379:methods; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011108:Polymers