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Sunitinib decreases the expression of KRT6A and SERPINB1 in 3D human epidermal models
Ayaka Yoshida1,2, Kazuhiro Yamamoto1, Takahiro Ishida3
1Department of Pharmacy, Kobe University Hospital, Kobe, Japan.
Abstract:
Hand-foot skin reaction (HFSR) is a common side effect caused by several tyrosine kinase inhibitors, including sunitinib. However, the nature of the cornifying factors related to the molecular biological mechanisms underlying HFSR remains poorly understood. We used human keratinocyte models to investigate the key cornifying factors for dermatological and biological abnormalities induced by sunitinib. On the basis of the results of microarray analysis using the three-dimensional (3D) human epidermal model, keratin (KRT)6A, serine protease inhibitor (SERPIN)B1, KRT5, and SERPIN Kazal-type 6 were selected as candidate genes related to HFSR. Sunitinib treatment significantly decreased the expression of SERPINB1 and KRT6A in the immunohistochemical staining of the 3D epidermal model. In PSVK1 cells, but not in normal human epidermal keratinocyte cells, both of which are human normal keratinocyte cell lines, sunitinib decreased the expression of KRT6A with a concomitant decrease in levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated p38 mitogen-activated protein kinase (MAPK). Inhibitors of the ERK and p38 MAPK signal pathways also significantly decreased KRT6A expression. Sunitinib-induced decrease in KRT6A expression was suppressed by the inhibition of glycogen synthase kinase-3β by enhancing ERK1/2 and p38 MAPK phosphorylation. Thus, sunitinib reduces the expression of KRT6A and SERPINB1 by inhibiting the ERK1/2 and p38 MAPK signalling pathways in the skin model. These changes in expression contribute to the pathology of HFSR.
Insights
Sunitinib, a tyrosine kinase inhibitor, causes hand-foot skin reaction by decreasing keratin KRT6A and SERPINB1 expression. This occurs through inhibition of ERK1/2 and p38 MAPK signaling pathways in skin cells, contributing to HFSR pathology.
Area of Science:
- Dermatology
- Molecular Biology
- Oncology
Background:
- Hand-foot skin reaction (HFSR) is a frequent side effect of sunitinib, a tyrosine kinase inhibitor.
- The precise molecular mechanisms and cornifying factors driving sunitinib-induced HFSR are not fully understood.
Purpose of the Study:
- To investigate the key cornifying factors and molecular pathways involved in sunitinib-induced HFSR using human keratinocyte models.
Main Methods:
- Utilized a three-dimensional (3D) human epidermal model for microarray analysis.
- Performed immunohistochemical staining to assess gene expression changes.
- Investigated the role of extracellular signal-regulated kinases (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) signaling pathways.
Main Results:
- Identified KRT6A, SERPINB1, KRT5, and SERPIN Kazal-type 6 as candidate genes for HFSR.
- Sunitinib significantly decreased SERPINB1 and KRT6A expression in the 3D epidermal model.
- Sunitinib reduced KRT6A expression by inhibiting ERK1/2 and p38 MAPK pathways, an effect modulated by glycogen synthase kinase-3β.
Conclusions:
- Sunitinib diminishes KRT6A and SERPINB1 expression via the ERK1/2 and p38 MAPK signaling pathways.
- These molecular alterations are implicated in the pathogenesis of hand-foot skin reaction.
