Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes

Jeong Hwan Yoon, Su Myung Jung, Seok Hee Park, Mitsuyasu Kato, Tadashi Yamashita, In Kyu Lee, Katsuko Sudo, Susumu Nakae, Jin Soo Han, Ok Hee Kim, Byung Chul Oh, Takayuki Sumida, Masahiko Kuroda, Ji Hyeon Ju, Kyeong Cheon Jung, Seong Hoe Park, Dae Kee Kim, Mizuko Mamura

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Varieties of transforming growth factor-β (TGF-β) antagonists have been developed to intervene with excessive TGF-β signalling activity in cancer. Activin receptor-like kinase5 (ALK5) inhibitors antagonize TGF-β signalling by blocking TGF-β 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-β 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.

Original languageEnglish
Pages (from-to)1720-1739
Number of pages20
JournalEMBO Molecular Medicine
Volume5
Issue number11
DOIs
StatePublished - Nov 2013

Keywords

  • ALK5 inhibitor
  • Eomes
  • Melanoma
  • Smad4
  • TGF-β

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