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Disorder of the mevalonate pathway inhibits calcium-induced differentiation of keratinocytes
Rui Jin1, Xin Luo1, Kang Luan1
1Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, Anhui 230022, P.R. China.
Abstract:
Mutation of genes encoding the enzymes of the mevalonate pathway cause a variety of diseases, including skin disorders. Mutation of four genes in this pathway, including mevalonate kinase, phosphomevalonate kinase, mevalonate diphosphate decarboxylase and farnesyl diphosphate synthase, have demonstrated to be responsible for porokeratosis (PK). However, the pathogenesis of PK remains unclear. In the present study, specific enzyme inhibitors of the mevalonate pathway, including pravastatin (PRA), alendronate (ALD), farnesyl transferase inhibitor (FTI‑277) and geranylgeranyl transferase inhibitor (GGTI‑298), were used to investigate the effect on differentiation of keratinocytes (KCs). Western blotting demonstrated that PRA, ALD, FTI‑277 or GGTI‑298 alone, or in combination, inhibited the expression level of calcium‑induced differentiation maker involucrin (INV) in KCs. ALD and PRA induced greater inhibition of INV compared with FTI‑277 and GGTI‑298 treatment. These inhibitors additionally influenced the expression levels of keratin1. Mechanistic studies revealed that treatment of cells with inhibitors decreased the expression levels of p53 and Notch1, and regulated activation of the mitogen activated protein kinase and phosphoinositide‑3‑kinase/protein kinase B signaling pathways. The results of the present study suggested that regulation of the mevalonate pathway may be necessary for differentiation of KCs, and the pathogenesis of disseminated superficial actinic PK.
Insights
Inhibiting the mevalonate pathway with drugs like pravastatin and alendronate disrupted keratinocyte differentiation, offering insights into porokeratosis pathogenesis.
Area of Science:
- Biochemistry
- Dermatology
- Molecular Biology
Background:
- Mutations in mevalonate pathway enzymes are linked to diseases, including porokeratosis (PK), a skin disorder.
- The precise pathogenesis of PK remains incompletely understood.
- The mevalonate pathway is crucial for cellular processes and disease development.
Purpose of the Study:
- To investigate the role of mevalonate pathway enzymes in keratinocyte (KC) differentiation.
- To explore the potential therapeutic targets for porokeratosis (PK).
- To elucidate the molecular mechanisms underlying PK pathogenesis.
Main Methods:
- Utilized specific mevalonate pathway inhibitors: pravastatin (PRA), alendronate (ALD), farnesyl transferase inhibitor (FTI‑277), and geranylgeranyl transferase inhibitor (GGTI‑298).
- Assessed the effect of these inhibitors on keratinocyte (KC) differentiation using Western blotting.
- Analyzed changes in key differentiation markers like involucrin (INV) and keratin 1.
- Investigated the impact on signaling pathways including p53, Notch1, MAPK, and PI3K/Akt.
Main Results:
- Pravastatin, alendronate, FTI‑277, and GGTI‑298 inhibited calcium-induced involucrin (INV) expression in keratinocytes (KCs).
- Alendronate and pravastatin demonstrated more potent inhibition of INV compared to FTI‑277 and GGTI‑298.
- Inhibitors affected keratin 1 expression levels.
- Treatment with inhibitors reduced p53 and Notch1 expression and modulated MAPK and PI3K/Akt signaling pathways.
Conclusions:
- Regulation of the mevalonate pathway is essential for keratinocyte (KC) differentiation.
- Mevalonate pathway dysregulation may contribute to the pathogenesis of disseminated superficial actinic porokeratosis (PK).
- Targeting the mevalonate pathway could be a potential therapeutic strategy for PK.