SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice

Park, Jin‐Hong; Ryu, Seung-Hee; Choi, Eun Kyung; Ahn, Seung Do; Park, Euisun; Choi, Kyung‐Chul; Lee, Sangwook

doi:10.18632/oncotarget.2878

Cited by 22 publications

(9 citation statements)

References 30 publications

(43 reference statements)

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“…PAI-1 knockout mice have better survival and intestinal function compared with wild-type mice in radiation-induced intestinal injury [25]. Finally, PAI-1 is closely regulated by TGF-β1, the cytokine that has a critical role in the RP process [22,26]. TGF-β1 can regulate PAI-1 expression via SMAD-dependent and -independent pathways in numerous fibrotic diseases [11,[27][28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in the plasminogen activator inhibitor‐1 gene are associated with an increased risk of radiation pneumonitis in lung cancer patients

Liu

Tang

et al. 2017

Cancer Medicine

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Plasminogen activator inhibitor‐1 (PAI‐1) plays a crucial role in the process of lung injury, although its association with radiation pneumonitis (RP) is unclear. We hypothesized that genetic variants in PAI‐1 may influence the risk of RP. In this study, 169 lung cancer patients were genotyped for six single‐nucleotide polymorphisms in PAI‐1 using the Sequenom MassARRAY system. The risk of RP was evaluated by Cox proportional hazards analyses. The cumulative RP probabilities by genotype were assessed using Kaplan–Meier analyses. Univariate and multivariate analyses revealed that PAI‐1:rs7242 GT/GG was correlated with an increased occurrence of grade ≥3 RP (crude hazard ratio = 3.331; 95% confidence interval, 1.168–9.497; P = 0.024). Our results indicated that PAI‐1:rs7242 in the 3′‐untranslated region of PAI‐1 can be a predictor of grade ≥3 RP before radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Genetic variants in the plasminogen activator inhibitor‐1 gene are associated with an increased risk of radiation pneumonitis in lung cancer patients

Liu

Tang

et al. 2017

Cancer Medicine

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“…The biological activity of TGF-β1 is regulated by diverse mechanisms and depends on transcriptional cofactors and the transcription potential of Smad2 and Smad3 [ 28 ]. In our previous results establishing the RIF mouse model, TGF-β1 mRNA was significantly increased in tissues of irradiated mouse 28 days after irradiation, and this could be detected for up to 3 months post-irradiation [ 47 ]. TGF-β1-mediated pro-fibrotic gene expression was suppressed by α-LA in mouse fibroblasts through inhibition of histone acetyltransferase, p300, and CBP [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Protective effect of α-lipoic acid against radiation-induced fibrosis in mice

et al. 2016

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Radiation-induced fibrosis (RIF) is one of the most common late complications of radiation therapy. We found that α-lipoic acid (α-LA) effectively prevents RIF. In RIF a mouse model, leg contracture assay was used to test the in vivo efficacy of α-LA. α-LA suppressed the expression of pro-fibrotic genes after irradiation, both in vivo and in vitro, and inhibited the up-regulation of TGF-β1-mediated p300/CBP activity. Thus, α-LA prevents radiation-induced fibrosis (RIF) by inhibiting the transcriptional activity of NF-κB through inhibition of histone acetyltransferase activity. α-LA is a new therapeutic methods that can be used in the prevention-treatment of RIF.

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“…Accordingly, TGF-β signaling-associated induction of the EMT is considered an important step in the progression of tumor metastasis. Conversely, blockade of TGF-β signaling has also been shown to dramatically inhibit invasion and metastasis and has been considered as a therapeutic approach in multiple types of cancer [ 6 , 13 – 15 ]. Therefore, further delineation of the mechanisms that regulate TGF-β signaling may provide new clues for the development of targeted cancer therapies.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of flotillin-1 promotes invasion and metastasis by activating TGF-β signaling in nasopharyngeal carcinoma

et al. 2015

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Metastasis is the main cause of cancer-related deaths. Nasopharyngeal carcinoma (NPC) is characterized by severe local invasion and high incidence of regional lymph node metastasis, which represents poor prognosis. However, the underlying mechanism that induces lymph node metastasis of NPC remains largely unknown. Herein, we report that flotillin-1 (FLOT1), a component of lipid raft, which was reported to be involved in tumor progression, was robustly upregulated in the NPC samples with lymph node metastasis. High FLOT1 expression was significantly associated with N classification as well as poorer overall and disease-free survivals in 169 archived clinical NPC samples. Overexpression of FLOT1 enhanced the migratory and invasive abilities of NPC cells in vitro, and more importantly, promoted invasion into the surrounding tissues and metastasis to lymph nodes in vivo. Whereas silencing of endogenous FLOT1 in NPC cells decreased the local invasion and metastasis to lymph nodes. Furthermore, FLOT1 induced the expression and secretion of TGF-β1, facilitated the activation of TGF-β/Smad3 signaling to effectuate epithelial-mesenchymal transition. Our findings present new evidence that FLOT1 plays an important role in promoting aggressive behavior of NPC and provide new insights into the regulatory mechanism of TGF-β signaling.

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SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice

Cited by 22 publications

References 30 publications

Genetic variants in the plasminogen activator inhibitor‐1 gene are associated with an increased risk of radiation pneumonitis in lung cancer patients

Genetic variants in the plasminogen activator inhibitor‐1 gene are associated with an increased risk of radiation pneumonitis in lung cancer patients

Protective effect of α-lipoic acid against radiation-induced fibrosis in mice

Upregulation of flotillin-1 promotes invasion and metastasis by activating TGF-β signaling in nasopharyngeal carcinoma

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