Expression and activity of alcohol and aldehyde dehydrogenases in melanoma cells and in melanocytes

Abstract

Disturbances in vitamin A metabolism are an important attribute of some cancer cells. Most evidence point that these disturbances lead to decreasing of the retinoic acid concentration in tumor cells. Up to now, in benign and malignant skin cells the features of vitamin A metabolism with its participating enzymes are not entirely understood. Alcohol and aldehyde dehydrogenases (ALDH) are involved in the retinol metabolism, oxidizing retinol, and retinal in retinoic acid or reducing retinal in retinol. In this work we investigated the expression and enzymatic activity of alcohol and ALDH in melanoma cells compared to their benign counterparts. We demonstrated that melanoma cell lines and melanocytes despite similar pattern of the enzyme expression, show different general ALDH activity. Retinal, the substrate of ALDH, could stimulate the ALDH activity through up-regulation of retinaldehyde dehydrogenase 1 and aldehyde dehydrogenase 6. Furthermore, we found that retinoids regulate alcohol dehydrogenase activity, probably via effects on alcohol dehydrogenase expression at the post-transcriptional level. We suggest that melanoma cells in contrast to melanocytes should favor the retinal reduction over its oxidation. The decreasing cellular amount of the precursor molecules of retinoic acid could result in a changed gene regulation in melanoma cells.

Knockdown of lecithin retinol acyltransferase increases all‐trans retinoic acid levels and restores retinoid sensitivity in malignant melanoma cells

“…Diminished ATRol esterification occurs in response to reduced LRAT expression or activity in various cancer cells (17)(18)(19)(20)(21)(22)(23). Recently, we identified human melanoma-specific alterations in the expression and activity of enzymes participating in retinoid metabolism (24,25). Interestingly, we found high LRAT expression and activity in human melanoma cells but not in benign melanocytes (25).…”

LRAT Overexpression Diminishes Intracellular Levels of Biologically Active Retinoids and Reduces Retinoid Antitumor Efficacy in the Murine Melanoma B16F10 Cell Line

“…Regulation of retinoid metabolism is complex [1,5,6], and aberrant vitamin A metabolism in cancer cells could represent a potential retinoid resistance mechanism in tumor cells. Accordingly, both the synthesis and metabolism of the bioactive metabolites of ATRol are sometimes impaired in cancer cells [10,11].…”

“…It was shown that cancer-specific modulations in retinoid metabolism reduce ATRA levels in cancer cells and that both the synthesis and metabolism of the bioactive metabolites of retinol are impaired in cancer cells relative to normal cells [10,11]. Recently, we identified alterations in retinoid metabolism in human melanoma cells [6,20]. ATRol can be oxidized to ATRA or alternatively be esterified into biologically inactive retinyl esters.…”

“…At the molecular level, ATRA binds and activates the retinoic acid receptors (RARs), which directly regulate the transcription of various target genes [1]. Intracellular retinoid levels are regulated by mechanisms that are not completely understood [5,6]. For ATRA synthesis, vitamin A (all- trans -retinol, ATRol) can be oxidated via all- trans -retinal (ATRal) as a metabolic intermediate [7,8].…”

Allergic or irritant contact dermatitis after patch testing with alcohol – that is the point

“…We consider it possible that a defect in aldehyde dehydrogenase leads, after 2 days of occlusion, to the topical accumulation of toxic substances such as acetaldehyde. The presence of these enzymes in the skin is well known (7,8,9), and deficiency in these enzymes leads to non-immunological irritant skin reactions (10)(11)(12)(13). With an occlusively applied 100% isopropanol solution, there might be sufficient substrate to provoke such an irritant reaction to acetaldehyde in predisposed individuals.…”