The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts

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.

Proline-dependent regulation of collagen metabolism

“…It suggests that exogenous Pro has lower than Gln influence on collagen biosynthesis. Recently we found that Pro deficiency resulting from a lack of Gln may be partly supplemented by recovery of Pro from imidodipeptides, intermediate products of protein degradation [54]. Thus, it can be concluded that fibroblasts prefer exogenous Gln, as an intermediate of proline for effective collagen biosynthesis.…”

Prolidase-proline oxidase axis is engaged in apoptosis induction by birch buds flavonol santin in endometrial adenocarcinoma cell line

“…The important role of proline recycled by prolidase has been shown in both normal and cancer cells. In dermal fibroblasts, cells addicted to proline due to extensive biosynthesis of extracellular matrix components, induction of prolidase stimulated TGFβ signalling ( Surazynski et al, 2010 ), and collagen biosynthesis ( Shim et al, 2012 ; Szoka et al, 2019 ). In breast cancer, proline released by prolidase was found to regulate HIF-1α expression ( Surazynski et al, 2013 ) and stimulate autophagy ( Zareba et al, 2020 ).…”

“…Hydrolysis of this bond in dipeptides released from proteins, and thus the final stage of protein degradation, is catalysed by cytoplasmic prolidase ( Wilk et al, 2017 ). The importance of prolidase for supplementing proline during its shortage has been demonstrated on the example of biosynthesis of collagen, a protein containing high proline residue content ( Shim et al, 2012 ; Szoka et al, 2015 ; Szoka et al, 2019 ).…”

“…Frontiers in Molecular Biosciences frontiersin.org et al, 2017). The importance of prolidase for supplementing proline during its shortage has been demonstrated on the example of biosynthesis of collagen, a protein containing high proline residue content (Shim et al, 2012;Szoka et al, 2015;Szoka et al, 2019). The p53-dependent activation of proline oxidase is a wellknown phenomenon.…”

In search of the needle in a haystack: Finding a suitable serum biomarker for monitoring disease activity of systemic sclerosis

“…Indeed, it's potentially life‐threatening and multiple organ sites‐affecting variant, systemic sclerosis (SSc), has long been in the spotlight of skin research. A number of novel pathways regulating fibroblast activation and tissue fibrosis beyond the profibrotic ‘master’ regulator transforming growth factor‐β 1 (TGF‐β 1 ) have been identified 71‐81 . For example, the expression of Dickkopf‐1, a natural Wnt antagonist, was shown to be altered in skin of patients with SSc 72 .…”