Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes
- Authors
- Yoon, Jeong-Hwan; Jung, Su Myung; Park, Seok Hee; Kato, Mitsuyasu; Yamashita, Tadashi; Lee, In-Kyu; Sudo, Katsuko; Nakae, Susumu; Han, Jin Soo; Kim, Ok-Hee; Oh, Byung-Chul; Sumida, Takayuki; Kuroda, Masahiko; Ju, Ji-Hyeon; Jung, Kyeong Cheon; Park, Seong Hoe; Kim, Dae-Kee; Mamura, Mizuko
- Issue Date
- Nov-2013
- Publisher
- WILEY
- Keywords
- ALK5 inhibitor; Eomes; melanoma; Smad4; TGF-
- Citation
- EMBO MOLECULAR MEDICINE, v.5, no.11, pp.1720 - 1739
- Journal Title
- EMBO MOLECULAR MEDICINE
- Volume
- 5
- Number
- 11
- Start Page
- 1720
- End Page
- 1739
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/14143
- DOI
- 10.1002/emmm.201302524
- ISSN
- 1757-4676
- Abstract
- Varieties of transforming growth factor- (TGF-) antagonists have been developed to intervene with excessive TGF- signalling activity in cancer. Activin receptor-like kinase5 (ALK5) inhibitors antagonize TGF- signalling by blocking TGF- receptor-activated Smad (R-Smad) phosphorylation. Here we report the novel mechanisms how ALK5 inhibitors exert a therapeutic effect on a mouse B16 melanoma model. Oral treatment with a novel ALK5 inhibitor, EW-7197 (2.5mg/kg daily) or a representative ALK5 inhibitor, LY-2157299 (75mg/kg bid) suppressed the progression of melanoma with enhanced cytotoxic T-lymphocyte (CTL) responses. Notably, ALK5 inhibitors not only blocked R-Smad phosphorylation, but also induced ubiquitin-mediated degradation of the common Smad, Smad4 mainly in CD8(+) T cells in melanoma-bearing mice. Accordingly, T-cell-specific deletion of Smad4 was sufficient to suppress the progression of melanoma. We further identified eomesodermin (Eomes), the T-box transcription factor regulating CTL functions, as a specific target repressed by TGF- via Smad4 and Smad3 in CD8(+) T cells. Thus, ALK5 inhibition enhances anti-melanoma CTL responses through ubiquitin-mediated degradation of Smad4 in addition to the direct inhibitory effect on R-Smad phosphorylation.
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