Overexpression of REIC/Dkk-3 in normal fibroblasts suppresses tumor growth via induction of interleukin-7.
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.
Sakaguchi
Masakiyo
M
Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikatachou, Okayama 700-8558, Japan.
Kataoka
Ken
K
Abarzua
Fernando
F
Tanimoto
Ryuta
R
Watanabe
Masami
M
Murata
Hitoshi
H
Than
Swe Swe
SS
Kurose
Kaoru
K
Kashiwakura
Yuji
Y
Ochiai
Kazuhiko
K
Nasu
Yasutomo
Y
Kumon
Hiromi
H
Huh
Nam-ho
NH
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
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