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

Abstract

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 sorafenibinduced 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.Cell Research (2020) 0:1-15; https://doi.

Identification of Beilschmiedia tsangii Root Extract as a Liver Cancer Cell–Normal Keratinocyte Dual-Selective NRF2 Regulator

“…Abnormal expression of matrix metalloproteinases such as MMP1 and MMP3 is known to affect the homeostasis of keratinocytes [ 31 , 32 , 33 ]. In addition, MMP1 and MMP3 can be induced by TNF-α and sorafenib treatment, respectively [ 34 , 35 ]. Moreover, these genes have been shown to be downregulated by NRF2 signaling [ 36 , 37 , 38 ].…”

Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity

“…The HaCaT cell line used in our studies is the most widely studied keratinocyte cell line. It is capable of proliferating and differentiating and often used for the mechanism studies of skin toxicity. − As a continuation of our interest in cutaneous toxicity mechanism study, − we sought to investigate the direct effect of different Akt subtypes on keratinocytes by employing HaCaT cells. Stable clones of Akt1, Akt2 or Akt3 silenced HaCaT cells were generated with short hairpin RNA (shRNA).…”

3D bioprinting of an implantable xeno-free vascularized human skin graft

“…Other cases of crosstalk between vascular ECs and KCs have been reported [34][35][36] . It was recently shown that soluble heparin-binding epidermal growth factor (s-HBEGF) released from vascular ECs activates the epidermal growth factor receptor (EGFR) on KCs and promotes stabilization of sirtuin 1 (SIRT1), an essential keratinization inducer 34 .…”

“…Other cases of crosstalk between vascular ECs and KCs have been reported [34][35][36] . It was recently shown that soluble heparin-binding epidermal growth factor (s-HBEGF) released from vascular ECs activates the epidermal growth factor receptor (EGFR) on KCs and promotes stabilization of sirtuin 1 (SIRT1), an essential keratinization inducer 34 . Although the proliferation of human primary KCs with s-HBEGF recombinant protein was almost unchanged in a cell survival assay, significant increase was detected in the mRNA levels of differentiation markers, corroborating the role of s-HBEGF in facilitating keratinization.…”