s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide
| Autor: | Ying Zhang, Ji Cao, Zhifei Xu, Ziying Zhao, Xiaochen Zhang, Su Zeng, Hao Yan, Bo Yang, Qiaojun He, Shenglin Ma, Peihua Luo, Jiangxia Du, Xueqin Chen, Yi Zhu |
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| Rok vydání: | 2019 |
| Předmět: |
Sorafenib
Keratinocytes Male Niacinamide Cancer therapy Models Biological Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Sirtuin 1 In vivo Epidermal growth factor medicine Animals HaCaT Cells Humans Mitogen-Activated Protein Kinase 9 Epidermal growth factor receptor Phosphorylation Molecular Biology 030304 developmental biology Aged Skin Aged 80 and over 0303 health sciences Gene knockdown Mice Inbred ICR biology Nicotinamide Kinase Foot Protein Stability Endothelial Cells Cell Biology Keratosis Middle Aged Hand Disease Models Animal Mechanisms of disease chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Female medicine.drug Heparin-binding EGF-like Growth Factor |
| Zdroj: | Cell Research |
| ISSN: | 1748-7838 |
| Popis: | Hand–foot skin reaction (HFSR), among the most significant adverse effects of sorafenib, has been limiting the clinical benefits of this frontline drug in treating various malignant tumors. The mechanism underlying such toxicity remains poorly understood, hence the absence of effective intervention strategies. In the present study, we show that vascular endothelial cells are the primary cellular target of sorafenib-induced HFSR wherein soluble heparin-binding epidermal growth factor (s-HBEGF) mediates the crosstalk between vascular endothelial cells and keratinocytes. Mechanistically, s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately gives rise to HFSR. The administration of s-HBEGF in vivo could sufficiently induce hyper-keratinization without sorafenib treatment. Furthermore, we report that HBEGF neutralization antibody, Sirt1 knockdown, and a classic SIRT1 inhibitor nicotinamide could all significantly reduce the sorafenib-induced HFSR in the mouse model. It is noteworthy that nicotinic acid, a prodrug of nicotinamide, could substantially reverse the sorafenib-induced HFSR in ten patients in a preliminary clinical study. Collectively, our findings reveal the mechanism of vascular endothelial cell-promoted keratinization in keratinocytes and provide a potentially promising therapeutic strategy for the treatment of sorafenib-induced HFSR. |
| Databáze: | OpenAIRE |
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