Retinoids, growth action

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

Mechanism of Action A second-generation retinoid that adjusts factors influencing epidermal proliferation, RNA/DNA synthesis, controls glycoprotein, and governs immune response. Therapeutic Effect Regulates keratinocyte growth and differentiation. 

Mechanism of Action A retinoid that decreases cohesiveness of follicular epithelial cells. Increases turnover of follicular epithelial cells. Bacterial skin counts are not altered. Transdermal Exerts its effects on growth and differentiation of epithelial cells. Antineoplastic Induces maturation, decreases proliferation of acute promyelocytic leukemia (APL) cells. Therapeutic Effect Causes expulsion of blackheads alleviates fine wrinkles, hyperpigmentation causes repopulation of bone marrow and blood by normal hematopoietic cells. 

The retinoids, a family of molecules that are related to retinol (vitamin A), are essential for vision, reproduction, growth, and maintenance of epithelial tissues. Retinoic acid, derived from oxidation of dietary retinol, mediates most of the actions of the retinoids, except for vision, which depends on retinal, the aldehyde derivative of retinol. 

Retinoids are classed as morphogens, small molecnles released from one type of cells that can affect the growth and differentiation of neighboring cells. Their normal roles in the hnman body are to indnce differentiation of some cells, stop the differentiation of others, and both snppress and indnce apoptosis in different cell types. Their diverse actions come from the diversity of their receptors. The two classes of retinoid receptors are retinoid X receptors (RXRs) and retinoic acid receptors (RARs), each with a, P, and y snbclasses. RXRs are versatile they bind to RARs and to other nnclear receptors such as thyroid hormone receptors. Once activated, the receptors act as transcription factors that in turn regulate the expression of genes that control ceUnlar growth and differentiation. ... 

Mehta PP, Bertram JS, Loewenstein WR (1989) The actions of retinoids on cellular growth correlate with their actions on gap junctional communication. Cell Biol 108 1053-1065... 

Mutants of the wild type S91-C2 melanoma cells have been isolated that are resistant to the antiproliferative action of retinoic acid (Lotan et al., 1983b). The mutant cells were also resistant to growth inhibition by retinol and a retinoidal benzoic acid derivative, suggesting a single growth-inhibitory mechanism common to all of these retinoids. Uptake of the retinoids was unimpaired in the mutant cells, and the cells had normal levels of CRABP. These results contrast with those of the retinoid-resistant embryonal carcinoma cell line mutants that were deficient in CRABP (Schindler et al., 1981). Eventually a mechanism of action of the retinoids will have to be described that can explain these diverse results, and mutants such as these should prove invaluable to such studies. 

Ultimately any formulation of a mechanism of action of the retinoids must be able to include retinoic acid and its derivatives. It is well-known that retinoic acid can substitute for retinol in supporting all the in vivo functions of the vitamin in growth and differentiation (with the exception of reproduction), and that retinoic acid, with few exceptions, is lOO-KKK) times as active as retinol in most cell-culture systems (see Section IV). Most of the various diverse biological assay systems discussed in Chapter 5, Vol. 1, show retinoic acid and its derivatives to be the most active members of the retinoid family. Furthermore, several studies have shown that retinoic acid can stimulate the incorporation of mannose into both glycoproteins and mannolipids in a variety of tissues and cells, both in vivo and in vitro (L. M. DeLuca, 1977 Sato eta/., 1978 Sasak eta/., 1980). Since it has been shown that the mixed anhydride retinoyl phosphate cannot serve as an acceptor of mannose from GDP-mannose (De Luca et al., 1977 Sato et al., 1978), an alternative intermediate must be found if this mechanism is to remain viable. 

Hie molecular hypothesis of retinoid action that is compatible with the broadest range of experimental data on retinoid control of cell growth, differentiation, and transformation is to suggest that retinoids modify genomic expression. This, of course is not a new idea. Almost IS years have passed since it was first demonstrated that retinoids might be controlling RNA synthesis (Zachman, 1%7 Johnson et al., 1969 Zile and DeLuca, 1970) however, these early studies were subject to criticism of experimental design. Thus, it is only lately that we have been able to address experimentally the questions of (1) which... 

Still other mechanisms of action might be considered. Rapaport etcd. (1982a,b) have shown that treatment of Swiss mouse 3T3 cells with retinoic acid significantly expands total cellular ATP pools in a dose-dependent manner, and that these changes alter functional compartmentalization of nuclear ATP pools (Schroder et al., 1983). It is proposed that these changes in nucleotide pools are directly responsible for the inhibition of DNA replication observed in these cells and that a similar mechanism might apply to other cells whose growth rate is modulated by retinoids (Schroder era/., 1983). 

RA and its isomers inhibit prostate epithelial cell growth [54]. Inhibition of RA metabolism raises plasma RA and inhibits relapse in the rat Dunning prostate cancer model [55]. RA decreases the concentrations of dihydrotestosterone, 3a-adiol and androsterone in serum, seems to cause a metabolic deviation away from the 5a-reductase path in liver [56], and causes a three-fold decrease in androgen receptor binding capacity [57]. Conversely, androgens affect the actions of retinoids by decreasing the mRNA of RARa approximately five-fold in prostate epithelia and 15 to 20-fold in seminal vesicles, while increasing it two-fold in kidney [58]. 

Activator protein-1 (AP-1) is an important transcription factor that figures in the inflammation response. AP-1 is a dimeric complex of the protooncoproteins jun and fos that is induced by growth factors, cytokines, tumor promoters, and sunlight [39]. Activation of AP-1 increases the transcription of cytokines, such as interleukin-2, and certain matrix metalloproteinases [40]. In the presence of t-RA, RARs can inhibit the actions of AP-1. Reciprocally, elevated expression of either the jun or fos components of AP-1 can prevent activation of RAREs by RARs. This repression of gene transcription, called transrepression, is a well-known mechanism for crosstalk between retinoid receptors and AP-1 [41-43]. The molecular mechanism of transrepression described for in vitro systems is dependent on the presence of t-RA and is believed to involve direct or indirect protein-protein interactions between retinoid receptors and AP-1 components (jun and fos), and/or competition between retinoid receptors and AP-1 for a common factor (or factors) required for their activities [42, 43]. However, this phenomenon studied in the context of photoaging of human skin in vivo has revealed a novel mechanism. 

It is important to state here that these compounds have not been found to increase communication between established tumor cells and normal cells [5] this would be consistent with their inability in the lOTl/2 system to inhibit expression of the transformed phenotype i.e. growth of tumor cells in a background of normal cells, and with the experimental animal data showing that these compounds are active in the post-initiation phase of carcinogenesis prior to the establishment of tumors. These observations would also be consistent with the lack of ability of retinoic acid to inhibit solid tumor growth in clinical trials in head and neck cancer [16]. Thus, in general, the actions of carotenoids and retinoids are considered to be preventive and not therapeutic. In a recent study of dysplastic regions of the oral cavity in patients with a prior history of oral carcinoma, we discovered that even in these pre-cancerous lesions major reductions in connexin 43 expression had occurred [17]. Studies are underway to determine if retinoids can counter this decrease. 

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