The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts. Issue 7 (6th June 2019)

• Record Type: Journal Article
• Authors: Szoka, Lukasz; Karna, Ewa; Andrulewicz‐Botulinska, Edyta; Hlebowicz‐Sarat, Kornelia; Palka, Jerzy A.
• Is Part Of: Experimental dermatology. Volume 28:Issue 7(2019)
• Page Start: 845
• Page End: 853
• Publication Date: 2019-06-06
• Subjects: Akt -- HIV protease inhibitors -- prolidase -- proline -- signalling; Dermatology -- Periodicals; 616.5
• DOI: 10.1111/exd.13956
• Languages: English
• ISSNs: 0906-6705

Abstract

Abstract: The mechanism for differential effects of human immune deficiency virus protease inhibitors (HIVPIs), nelfinavir (NEL) and indinavir (IND) on collagen metabolism disturbances was studied in human skin fibroblasts. It has been considered that HIVPIs‐dependent deregulation of collagen biosynthesis involves prolidase (an enzyme providing proline for collagen biosynthesis), glutamine (Gln) (a substrate for proline biosynthesis), nuclear factor‐κB (NF‐κB) (a transcription factor that inhibit expression of type I collagen genes), β1 integrin receptor and Akt signalling. It was found that NEL impaired collagen biosynthesis and the process was more pronounced in the presence of Gln, while IND stimulated collagen biosynthesis. NEL‐dependent inhibition of collagen biosynthesis was accompanied by massive intracellular accumulation of type I collagen, while IND slightly induced this process. This effect of NEL was reversed by ascorbic acid but not N‐acetylcysteine. The mechanism for the NEL‐dependent defect in collagen metabolism was found at the level of prolidase activity, β1 integrin signalling and NF‐κB. NEL inhibited expression of β1 integrin receptor, Akt and ERK1/2 and increased expression of p65 NF‐κB. However, inhibitors of p65 NF‐κB did not prevent NEL‐dependent inhibition of collagen biosynthesis suggesting that this transcription factor is not involved in studied mechanism. Using PI3K inhibitor wortmannin that prevent phosphorylation of Akt revealed that NEL‐dependent inhibition of Akt results in inhibition of collagen biosynthesis. The data suggest that differential effect of NEL and IND on collagen metabolism involves NEL‐dependent down‐regulation of Akt signalling and proline availability for collagen biosynthesis.