Differential effects of retinol and retinoic acid on cell proliferation: A role for reactive species and redox-dependent mechanisms in retinol supplementation

Abstract

While some authors suggest that retinoids are potential anti-proliferative and antioxidant agents, evidence has suggested those present pro-oxidant properties, which might lead to malignant proliferation. These discordances stimulated one to investigate the proliferative/anti-proliferative properties of two major retinoids, retinol (ROH) and retinoic acid (RA). In Sertoli cells, ROH increased proliferation while RA was anti-proliferative. ROH increased DNA synthesis, decreased p21 levels and induced cell cycle progression. ROH increased reactive species (RS) production and stimulated p38, JNK1/2 and ERK1/2 MAPKs activation. Antioxidant treatment with Trolox blocked ROH-induced RS production, MAPKs activation and proliferation; MAPKs inhibition blocked proliferation. The potential sites of RS indicate that ROH-induced RS is promoted via mitochondria and xanthine oxidase. In contrast, RA induced neither RS production nor MAPKs activation. RA decreased DNA synthesis and increased p21 leading to cell arrest. Overall, data show that ROH, but not RA, is able to induce proliferation through non-classical and redox-dependent mechanisms.

Influence of a 50 Hz magnetic field and of all-trans‑retinol on the proliferation of human cancer cell lines

“…Whether or not this proliferative response involves mechanisms related to oxidative stress remains to be elucidated. As for the differences observed in the ROL dose-response patterns displayed by HepG2 and NB69, they support previously reported indications that ROL present different active properties in biological systems (51). The biphasic pattern of proliferarive/ antiproliferative response of NB69 as a function of the ROL concentration, has also been described in different cell types treated with retinoids (54,55) or with other agents that exhibit antitumor activity (56).…”

“…Also using Sertoli cells, other studies have reported that 7-10 µM ROL induces mitogenic signaling, accompanied by increased DNA synthesis and focus formation, mediated by superoxide anion generation. This effect is reversed by antioxidant treatment (50,51). By contrast, lower ROL concentrations 1-5 µM, which are considered to be within the physiological range for Sertoli cells (52) increased neither reactive species production nor proliferation.…”

Retinoic acid metabolism, signaling, and function in the adult testis

“…In contrast, treatment of cultured Sertoli cells with retinol stimulated proliferation, as measured by increased DNA synthesis and decreased p21 levels. These data also indicated that induced proliferation was mediated through nonclassical retinoid signaling and redox-dependent mechanisms [89,90]. A more recent report from Nicholls and colleagues has extended these studies and linked RA and activin to the regulation of Sertoli cell terminal differentiation [80].…”

“…Most of the data to implicate RA in regulating Sertoli cell terminal differentiation has been generated from cultures of primary rodent Sertoli cells. When both Buzzard and colleagues and Zanotto-Filho and colleagues treated primary Sertoli cell cultures with RA, they observed a suppressive effect on proliferation, rate of division, and DNA synthesis; an accumulation of cell cycle inhibitors (p27Kip1 and p21Cip1), and increased expression of markers of Sertoli cell differentiation (Gata1 and Gata4) [88,89]. In contrast, treatment of cultured Sertoli cells with retinol stimulated proliferation, as measured by increased DNA synthesis and decreased p21 levels.…”

Hipervitaminose induzida pela suplementação de vitamina A em rações para pós-larvas de tilápia do Nilo

“…Uma das características bioquímicas da vitamina A é a sua insolubilidade em água, o que possibilita o seu armazenamento no fígado e nas células de Sertoli, porém dificultam a sua excreção (HU et al, 2006;ZANOTTO-FILHO;SCHRÖDER;MOREIRA, 2008). Devido a estas características, a sua ingestão excessiva pode provocar a hipervitaminose e/ou efeitos tóxicos (CAMPECHE, 2003).…”