Cryptotanshinone from Salvia miltiorrhiza Roots Reduces Cytokeratin CK1/10 Expression in Keratinocytes by Activation of Peptidyl-prolyl-cis-trans-isomerase FKBP1A

Stefan Esch; Simone König; Bertan Bopp; Joachim Jose; Simone Brandt; Andreas Hensel

doi:10.1055/a-0660-0441

Planta Medica, Table of Contents

Planta Med 2019; 85(07): 552-562
DOI: 10.1055/a-0660-0441

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

Cryptotanshinone from Salvia miltiorrhiza Roots Reduces Cytokeratin CK1/10 Expression in Keratinocytes by Activation of Peptidyl-prolyl-cis-trans-isomerase FKBP1A

Stefan Esch

¹University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany

,

Simone König

²University of Münster, Interdisciplinary Centre for Clinical Research, Core Unit Proteomics, Münster, Germany

,

Bertan Bopp

³University of Münster, Institute of Pharmaceutical and Medicinal Chemistry, Münster, Germany

,

Joachim Jose

³University of Münster, Institute of Pharmaceutical and Medicinal Chemistry, Münster, Germany

,

Simone Brandt

¹University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany

,

Andreas Hensel

¹University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany

› Author Affiliations

Abstract

Cryptotanshinone (CTS) (1 µM) from the roots of Salvia miltiorrhiza exerts a strong influence on the terminal differentiation of human keratinocytes (HaCaT cell line, primary natural human keratinocytes) and downregulates the expression of differentiation-specific cytokeratins CK1 and CK10 on protein and gene level. Other differentiation specific proteins as involucrin, filaggrin, loricrin, and transglutaminase were not affected to a higher extent. CTS (1 µM) did not influence the cell viability and the proliferation of keratinocytes. Using a combination of drug affinity response target stability assay in combination with a proteomic approach and multivariate statistics for target elucidation, peptidyl-prolyl-cis-trans-isomerase FKBP1A (known target of inhibitors such as tacrolimus or rapamycin) was addressed as potential molecular target of CTS. The interaction of CTS with FKBP1A was additionally shown by thermal shift and enzymatic activity assays. Interestingly, CTS served as an activator of FKBP1A, which led to a reduced activity of the TGFβ receptor pathway and therefore to a diminished CK1 and CK10 expression. The combination of the FKBP1A activator CTS with the inhibitor tacrolimus neutralized the effects of both compounds. From these data, a potential dermatological use of CTS and CTS-containing plant extracts (e.g., hydroalcoholic extract from the roots of S. miltiorrhiza) for keratinopathic ichthyosis, a disease characterized by overexpression of CK1 and CK10, is discussed. This study displays an experimental strategy for combining phytochemical aspects on active natural products with systematic identification of molecular targets on gene, protein, and cell level.

Key words

CFKBP1A - cryptotanshinone - differentiation - keratinocytes - Salvia miltiorrhiza - Lamiaceae - TGFβ receptor

Full Text

References

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