An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis

• Published in: Biochemical and biophysical research communications Vol. 375; no. 4; pp. 614 - 618
• Main Authors: Abarzua, Fernando, Kashiwakura, Yuji, Takaoka, Munenori, Watanabe, Masami, Ochiai, Kazuhiko, Sakaguchi, Masakiyo, Iwawaki, Takao, Tanimoto, Ryuta, Nasu, Yasutomo, Huh, Nam-ho, Kumon, Hiromi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31-10-2008
• Subjects: Amino Acid Sequence; Animals; Apoptosis; Cationic biodegradable polymer; Cell Line, Tumor; Endoplasmic Reticulum - metabolism; ER stress; Gene therapy; Genes, Tumor Suppressor; Genetic Therapy; Humans; Intercellular Signaling Peptides and Proteins - genetics; Male; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Polymers - chemistry; Prostatic Neoplasms - therapy; REIC/Dkk-3; Sequence Deletion; Transfection - methods; Truncation form; Xenograft Model Antitumor Assays; ER stress; Truncation form; REIC/Dkk-3; Gene therapy; Cationic biodegradable polymer
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.08.079

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 (
1–78REIC/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
1–78REIC/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.