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The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts
Author(s) -
Szoka Lukasz,
Karna Ewa,
AndrulewiczBotulinska Edyta,
HlebowiczSarat Kornelia,
Palka Jerzy A.
Publication year - 2019
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.13956
Subject(s) - chemistry , protein kinase b , biochemistry , collagen receptor , microbiology and biotechnology , signal transduction , integrin , biology , receptor
The mechanism for differential effects of human immune deficiency virus protease inhibitors ( HIVPI s), nelfinavir ( NEL ) and indinavir ( IND ) on collagen metabolism disturbances was studied in human skin fibroblasts. It has been considered that HIVPI s‐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), β 1 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, β 1 integrin signalling and NF ‐κB. NEL inhibited expression of β 1 integrin receptor, Akt and ERK 1/2 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 PI 3K 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.