Epoxytiglianes induce keratinocyte wound healing responses via classical protein kinase C activation to promote skin re-epithelialization.

Autor: Moses RL; Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, UK; Melbourne Dental School, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia., Woods EL; Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, UK., Dally J; Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, UK., Johns JP; Cancer Drug Mechanisms Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Knäuper V; Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, UK., Boyle GM; Cancer Drug Mechanisms Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Gordon V; QBiotics Group, Yungaburra, Queensland, Australia., Reddell P; QBiotics Group, Yungaburra, Queensland, Australia., Steadman R; Wales Kidney Research Unit, Division of Infection and Immunity, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, UK., Moseley R; Disease Mechanisms Group, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, UK. Electronic address: MoseleyR@cardiff.ac.uk.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2024 Dec; Vol. 230 (Pt 2), pp. 116607. Date of Electronic Publication: 2024 Nov 01.
DOI: 10.1016/j.bcp.2024.116607
Abstrakt: Epoxytiglianes are a novel class of diterpene esters. The prototype epoxytigliane, EBC-46 (tigilanol tiglate), is a potent anti-cancer agent in clinical development for local treatment of a range of human and animal tumors. EBC-46 also consistently promotes wound re-epithelialization at the treatment sites, mediated via activation of classical protein kinase C (PKC) isoforms. We have previously shown that epoxytiglianes stimulate proliferative and wound repopulation responses in immortalized human skin keratinocytes (HaCaTs) in vitro, abrogated by pan-PKC inhibitor, bisindolylmaleimide-1. In this study, we further investigate the specific PKC isoforms responsible for inducing such wound healing responses, following HaCaT treatment with 1.51 nM-15.1 µM EBC-46 or analogue, EBC-211. Classical PKC inhibition by GӦ6976 (1 μM), significantly attenuated epoxytigliane induced, HaCaT proliferation and wound repopulation at all epoxytigliane concentrations. PKC-βI/-βII isoform inhibition by enzastaurin (1 μM), significantly inhibited HaCaT proliferation and wound repopulation responses induced by both epoxytiglianes, especially at 1.51-151 nM. PKC-α inhibitor, Ro 31-8220 mesylate (10 nM), exerted lesser inhibitory effects on HaCaT responses. Epoxytigliane changes in key keratin (KRT17) and cell cycle (cyclin B1, CDKN1A) protein levels were partly attenuated by GӦ6976 and enzastaurin. GӦ6976 also inhibited increases in matrix metalloproteinase (MMP-1, MMP-7, MMP-10) activities. Phospho-PKC (p-PKC) studies confirmed that epoxytiglianes transiently activated classical PKC isoforms (p-PKCα, p-PKC-βI/-βII, p-PKCγ) in a dose- and time-dependent manner. By identifying how epoxytiglianes stimulate classical PKCs to facilitate keratinocyte healing responses and re-epithelialization, these findings support further epoxytigliane development as topical therapeutics for clinical situations involving impaired re-epithelialization, such as non-healing wounds in skin.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was conducted with financial support from QBiotics Group. P.R. and V.G. are employees and possess ownership interests in QBiotics Group. R.M., R.S., R.L.M., P.R., V.G., G.M.B. and QBiotics Group have filed patents on the work disclosed within this manuscript. E.L.W., J.D., J.P.J. and V.K. have no conflict of interests to declare.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: