title: Overexpression of REIC/Dkk-3 in normal fibroblasts suppresses tumor growth via induction of interleukin-7.
abstract: 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 IRE1alpha, 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.
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikatachou, Okayama 700-8558, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Kataoka
authors.forename: Fernando
authors.initials: F
authors.lastname: Abarzua
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tanimoto
authors.forename: Masami
authors.initials: M
authors.lastname: Watanabe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murata
authors.forename: Swe Swe
authors.initials: SS
authors.lastname: Than
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kurose
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kashiwakura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ochiai
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nasu
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumon
authors.forename: Nam-ho
authors.initials: NH
authors.lastname: Huh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines; D004721:Endoplasmic Reticulum / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000473:pathology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; C494257:IRF1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D050856:Interferon Regulatory Factor-1; D015851:Interleukin-7; D050794:STAT1 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human