Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis
AbstractIdiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting Skp2 suppressed pulmonary fibrosis in a bleomycin (BLM)-induced mouse model and found that pulmonary fibrosis was significantly suppressed in Skp2-deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in Skp2-deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild-type mice, but recovered in Skp2−/− mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by Skp2-deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL-P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF. View Full-Text
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Mikamo, M.; Kitagawa, K.; Sakai, S.; Uchida, C.; Ohhata, T.; Nishimoto, K.; Niida, H.; Suzuki, S.; Nakayama, K.I.; Inui, N.; Suda, T.; Kitagawa, M. Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis. Int. J. Mol. Sci. 2018, 19, 474.
Mikamo M, Kitagawa K, Sakai S, Uchida C, Ohhata T, Nishimoto K, Niida H, Suzuki S, Nakayama KI, Inui N, Suda T, Kitagawa M. Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis. International Journal of Molecular Sciences. 2018; 19(2):474.Chicago/Turabian Style
Mikamo, Masashi; Kitagawa, Kyoko; Sakai, Satoshi; Uchida, Chiharu; Ohhata, Tatsuya; Nishimoto, Koji; Niida, Hiroyuki; Suzuki, Sayuri; Nakayama, Keiichi I.; Inui, Naoki; Suda, Takafumi; Kitagawa, Masatoshi. 2018. "Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis." Int. J. Mol. Sci. 19, no. 2: 474.
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