Overexpression of REIC/Dkk-3 in Normal Fibroblasts Suppresses Tumor Growth via Induction of Interleukin-7S

• Published in: The Journal of biological chemistry 2009-05, Vol.284 (21), p.14236-14244
• Main Authors: Sakaguchi, Masakiyo, Kataoka, Ken, Abarzua, Fernando, Tanimoto, Ryuta, Watanabe, Masami, Murata, Hitoshi, Than, Swe Swe, Kurose, Kaoru, Kashiwakura, Yuji, Ochiai, Kazuhiko, Nasu, Yasutomo, Kumon, Hiromi, Huh, Nam-ho
• Format: Article
• Language: English
• Subjects: Molecular Basis of Cell and Developmental Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M808002200

We previously showed that the tumor suppressor gene REIC / Dkk-3 , when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through a mechanism triggered by endoplasmic reticulum stress. Adenovirus vectors show no target cell specificity and thus may elicit unfavorable side effects through infection of normal cells even upon intra-tumoral injection. In this study, we examined possible effects of Ad-REIC on normal cells. We found that infection of normal human fibroblasts (NHF) did not cause apoptosis but induced production of interleukin (IL)-7. The induction was triggered by endoplasmic reticulum stress and mediated through IRE1α, ASK1, p38, and IRF-1. When Ad-REIC-infected NHF were transplanted in a mixture with untreated human prostate cancer cells, the growth of the cancer cells was significantly suppressed. Injection of an IL-7 antibody partially abrogated the suppressive effect of Ad-REIC-infected NHF. These results indicate that Ad-REIC has another arm against human cancer, an indirect host-mediated effect because of overproduction of IL-7 by mis-targeted NHF, in addition to its direct effect on cancer cells.