The Hsp27-Mediated IkBα-NFκB Signaling Axis Promotes Radiation-Induced Lung Fibrosis

Kim, Jee Youn; Jeon, Seulgi; Yoo, Young Joon; Jin, Hee Kyung; Won, Hee Yeon; Yoon, Kyeonghee; Hwang, Eun Sook; Lee, Yoon Jin; Na, Younghwa; Cho, Jaeho; Lee, Yun Sil

doi:10.1158/1078-0432.ccr-18-3900

Cited by 44 publications

(42 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we predominantly investigated the anti-fibrotic effects of LXA 4 -2 and 6 weeks after 75 Gy of IR-by immunostaining for α-SMA, TGF-β, and Twist and by MT staining for collagen expression. Two weeks after exposure to 75 Gy IR, our experimental model manifested radiation pneumonitis with radiation-induced inflammation, whereas 6 weeks after 75 Gy IR exposure, the model manifested IR-induced lung fibrosis with increased fibrosis marker and collagen expression 8,26,28 . To investigate the crosstalk between FPR2, IR-induced inflammatory responses, and fibrosis-related gene expression, we observed NF-κB and SBE promoter activity in the background of IR.…”

Section: Discussionmentioning

confidence: 85%

“…Here, we examined the anti-inflammatory and anti-fibrotic properties of LXA 4 using a mouse model of RILI, wherein ablative radiation doses were delivered to the focal lung area using an image-guided IR system 6 , 7 , 26 – 28 . We also investigated whether LXA 4 regulates proteins that are important for EMT, particularly whether the crosstalk between LXA 4 -ALX/FPR2 and TGF-β/Smad signaling plays a key role in EMT.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

et al. 2020

Self Cite

View full text Add to dashboard Cite

Radiation therapy is an important modality in the treatment of lung cancer, but it can lead to radiation pneumonitis, and eventually radiation fibrosis. To date, only few available drugs can effectively manage radiation-induced pulmonary fibrosis. Lipoxins are endogenous molecules exhibit anti-inflammatory and pro-resolving effects. These molecules play a vital role in reducing excessive tissue injury and chronic inflammation; however, their effects on radiation-induced lung injury (RILI) are unknown. In this study, we investigated the effects of lipoxin A 4 (LXA 4) on RILI using our specialized small-animal model of RILI following focal-ablative lung irradiation (IR). LXA 4 significantly inhibited immune-cell recruitment and reduced IR-induced expression of pro-inflammatory cytokines and fibrotic proteins in the lung lesion sites. In addition, micro-CT revealed that LXA 4 reduced IR-induced increases in lung consolidation volume. The flexiVent TM assays showed that LXA4 significantly reversed IR-induced lung function damage. Moreover, LXA4 downregulated the activities of NF-κB and the Smad-binding element promoters. The expression of FPR2, an LXA 4 receptor, increased during the development of IR-induced pulmonary fibrosis, whereas silencing of endogenous LXA 4 using an antagonist (WRW4) or FPR2 siRNA resulted in impaired development of pulmonary fibrosis in response to IR. Collectively, these data suggest that LXA 4 could serve as a potent therapeutic agent for alleviating RILI.

show abstract

Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this report, we found that IR could induce the up-regulation of RAC1 expression and activity via activating the PI3K/AKT signaling pathway (36,(48)(49)(50). Interestingly, IRinduced EMT is regulated by RAC1, a member of the Rho family of small guanosine triphosphatases (GTPases) that has been shown to play a critical role in cytoskeleton reorganization, cell migration and cell survival (51,52). Thus, we raised the possibility that RAC1 might be an important regulator in the process of IR-induced EMT in lung cancer.…”

Section: Discussionmentioning

confidence: 98%

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

Tan

Wang

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

Radiation therapy is a common and acceptable approach for lung cancer. Although the benefit of ionizing radiation (IR) is well-established, cancer cells can still survive via pro-survival and metastasis signaling pathways. Ras related C3 botulinum toxin substrate1 (RAC1), a member of Rho family GTPases, plays important roles in cell migration and survival. In the present study, we investigated the effects of RAC1 on the survival of lung cancer cells treated with irradiation. The results showed RAC1 is overexpressed in lung cancer cells and promoted cell proliferation and survival. Furthermore, IR induced RAC1 expression and activity via the activation of PI3K/AKT signaling pathway, and then enhancing cell proliferation, survival, migration and metastasis and increasing levels of epithelial-to-mesenchymal transition (EMT) markers, which facilitated the cell survival and invasive phenotypes. In addition, overexpression of RAC1 attenuated the efficacy of irradiation, while inhibition of RAC1 enhanced sensitivity of irradiation in xenograft tumors in vivo. Collectively, we further found that RAC1 enhanced radioresistance by promoting EMT via targeting the PAK1-LIMK1-Cofilins signaling in lung cancer. Our finding provides the evidences to explore RAC1 as a therapeutic target for radioresistant lung cancer cells.

show abstract

“…Inhibition of HSP27 using a recently identified small-molecule inhibitor, J2, induces crosslinking of HSP27 attenuated RIPF development. Mechanism underlying HSP27-mediated fibrosis development is IkBa-NFkB signaling activation, which is involved in the EMT process ( Table 3 ) [ 103 ].…”

Section: Therapeutic Targets and Their Inhibitors In Ripfmentioning

confidence: 99%

Radiation-Induced Lung Fibrosis: Preclinical Animal Models and Therapeutic Strategies

Jin

Yoo

Kim

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Radiation-induced lung injury (RILI), including acute radiation pneumonitis and chronic radiation-induced lung fibrosis, is the most common side effect of radiation therapy. RILI is a complicated process that causes the accumulation, proliferation, and differentiation of fibroblasts and, finally, results in excessive extracellular matrix deposition. Currently, there are no approved treatment options for patients with radiation-induced pulmonary fibrosis (RIPF) partly due to the absence of effective targets. Current research advances include the development of small animal models reflecting modern radiotherapy, an understanding of the molecular basis of RIPF, and the identification of candidate drugs for prevention and treatment. Insights provided by this research have resulted in increased interest in disease progression and prognosis, the development of novel anti-fibrotic agents, and a more targeted approach to the treatment of RIPF.

show abstract

The Hsp27-Mediated IkBα-NFκB Signaling Axis Promotes Radiation-Induced Lung Fibrosis

Cited by 44 publications

References 49 publications

LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

Radiation-Induced Lung Fibrosis: Preclinical Animal Models and Therapeutic Strategies

Contact Info

Product

Resources

About