Sorafenib induces autophagy in human myeloid dendritic cells and prolongs survival of skin allografts

Jiunn Chang Lin, Wei Pang Huang, Chien Liang Liu, Jie Jen Lee, Tsang Pai Liu, Wen Chin Ko, Yu Chuen Huang, Ming Ling Hsu, Chih Hsiung Wu, Yu Jen Chen

研究成果: 雜誌貢獻文章同行評審

10 引文 斯高帕斯(Scopus)

摘要

Background. Sorafenib, a multikinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, has been reported inhibitory on the function of dendritic cells. This study was aimed to determine the effects of sorafenib on inducing autophagy and immunomodulatory activity and its implication on graft rejection. Methods. Cell viability and surface antigens were examined by 7-amino-actinomycin D and flow cytometric analysis. Autophagy was characterized using light microscopy and transmission electron microscopy for morphology, Western blotting for LC3B-I lipidation and mammalian target of rapamycin signaling molecules, and immunofluorescence staining for endogenous LC3B, GFP-LC3 transfection, and acidic component vacuoles. Skin allograft in mice was used as an experimental transplantation rejection model. Soluble factors contained in culture medium and serum were measured by enzyme-linked immunosorbent assay. Results. We found that sorafenib inhibited the viability of dendritic cells accompanied by morphologic changes characteristic of autophagy and immature differentiation. This autophagic effect induced by sorafenib was validated by LC3B-I lipidation and autophagosome accumulation. Sorafenib treatment was associated with the down-regulation of phosphorylated mammalian target of rapamycin and its downstream substrate p70S6K. We next performed skin graft model to testify the role of sorafenib-induced immature and autophagic dendritic cells. Intriguingly, sorafenib prolonged the survival of skin allograft without major toxicity. Blockade of autophagic flux by chloroquine partially diminished the protective effect of sorafenib, indicating an autophagy-related mechanism in vivo. Conclusion. This study suggests that sorafenib, in addition to being an anticancer agent, may have potential to be developed as a new category of immunosuppressant drugs acting via autophagy induction of dendritic cells.

原文英語
頁(從 - 到)791-800
頁數10
期刊Transplantation
95
發行號6
DOIs
出版狀態已發佈 - 五月 27 2013

ASJC Scopus subject areas

  • Transplantation

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