Retinoids and their receptors in cancer development and chemoprevention
Introduction
The term retinoids, first coined by Sporn in 1976 [1], generally refers to the entire set of compounds including both naturally occurring and synthetic vitamin A (retinol) metabolites and analogs. Retinoids are physiological regulators of a large number of essential biological processes including embryonic development, vision, reproduction, bone formation, metabolism, hematopoiesis, differentiation, proliferation, and apoptosis [2], [3], [4], [5]. Pharmacologically, they have been recognized as modulators of cell growth, differentiation, and apoptosis. In addition, they were shown to suppress carcinogenesis in a variety of tissue types, e.g., oral cancer, skin, bladder, lung, prostate, and breast cancers in experimental animals [4], [5], [6]. Clinically, they are able to reverse premalignant lesions and inhibit the development of second primary tumors in the head and neck area and in xeroderma pigmentosum patients [7]. These findings further confirmed that retinoids might be useful in both chemotherapy and chemoprevention of human cancers. Indeed, all-trans-retinoic acid (ATRA), a natural vitamin A metabolite, was approved by the FDA for the treatment of patients with acute promyelocytic leukemia (APL).
A strong relationship between vitamin A and cancer development has been established by numerous investigations over the last few decades. Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens [8]. Further, epidemiological studies have indicated that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer [9]. These observations have led to the hypothesis that physiological levels of retinoids guard the organism against the development of premalignant and malignant lesions.
An extensive research effort has been dedicated to elucidate the molecular and cellular mechanism of retinoid action. Especially, the discovery and cloning of the retinoid receptors revolutionized our understanding as to how retinoids exert their pleiotropic effects [10], [11]. It is generally thought that the effects of retinoid are mainly mediated by nuclear retinoid receptors, which are members of the steroid hormone receptor superfamily [12]. There are two types of retinoid receptors: retinoic acid receptors (RARs), which bind to ATRA and 9-cis retinoic acid (9CRA) with similar affinities, and retinoid X receptors (RXRs), which bind 9CRA. Each type of nuclear retinoid receptor includes three subtypes: α, β, and γ, with distinct amino- and carboxy-terminal domains [10], [11]. Further, for each RAR subtype, there are several isoforms that differ from one another in their A region, which arise from the differential usage of promoters and alternative splicing [10]. There are two major isoforms for RARα (α1 and α2) and for RARγ (γ1 and γ2), and four major forms for RARβ (β1–β4). Similarly, several isoforms differing from one another in their amino-terminal region have been identified for RXRα (α1 and α2), RXRβ (β1 and β2), and RXRγ (γ1 and γ2) [10]. Like other members of this family, the retinoid receptors are ligand-activated, DNA-binding trans-acting, transcription-modulating proteins. RARs can form heterodimers with RXRs; the heterodimers can bind to specific DNA sequence-RA response elements (RAREs), characterized by direct repeats of (A/G)GGTCA separated by five nucleotides (DR5) (e.g. RARβ2 gene) or by one or two nucleotides (DR1 or DR2) (e.g. CRABP II and CRBP I genes), with RXR bound in the 5′ and RAR in the 3′ position [10], [11].
The recent discovery of nuclear receptor associated proteins (co-activators and co-repressors) provided details on how DNA-bound unliganded and liganded receptor dimers influence transcription of target genes. In the absence of RAR ligand (e. g. ATRA), the RXR/RAR heterodimer recruits nuclear receptor co-repressor proteins N-CoR or SMRT, mSin3, and histone deacetylase [13], [14], [15]. This may lead to histone deacetylation and formation of an inactive chromatin structure preventing transcription. Ligand binding causes the dissociation of co-repressor proteins and promotes association of co-activators (e. g. CBP/p300 and ACTR) with the liganded receptors. This binding results in chromatin decondensation and activation of gene transcription (reviewed in Ref. [16]). Remarkably, several of the co-activators and co-repressors are shared by multiple signaling pathways. For example, CBP has been implicated in AP-1, p53, STAT signaling among others and Sin3 and HDAC-1 are involved in Mad–Max signaling [17], [18], [19], [20], [21]. This model of transcriptional activation and repression by nuclear receptors and their co-factors provides a direct link not only among multiple signaling pathways critical in cellular proliferation, differentiation and apoptosis but also among these pathways and the chromatin structure of target genes.
In addition to forming a heterodimer with RARs, RXRs can form heterodimers with several nuclear receptors including thyroid hormone receptors, vitamin D receptor, peroxisomal proliferator–activator receptors, farnesoid X receptors and liver X receptors. Thus, RXR is a common partner in at least 11 distinct signaling pathways (reviewed in Ref. [22]). Therefore, RXR-selective retinoids (rexinoids) may have additional applications beyond cancer for prevention and treatment of diseases such as diabetes, obesity and atherosclerosis. In this review, we will only discuss their role in cancer development and chemoprevention.
Section snippets
Modulation of retinoid signaling in cancer development
Epidemiological investigations showed an inverse relation between the risk of developing cancer and the dietary vitamin A intake. Vitamin A deficiency has been associated with increased incidence of cancer of several organs and tissues. As early as 1925, Wolbach and Howe [23] found that vitamin A deficiency might result in sqamous metaplasia in bronchi. This change may contribute to carcinogenesis. In the 1970s, it was demonstrated that retinoids can alter the premalignant phenotype of cells
Retinoids as cancer chemopreventive agents
The rationale for the use of retinoids in cancer chemoprevention is based mainly on a strong relationship between retinoids and cancer development established by numerous investigations over the last couple of decades as we demonstrated above. Promising data derived from experimental animal models and successful clinical trials treating premalignant lesions or preventing second primary tumors further prove their potential as cancer chemopreventive agents.
Conclusions
Retinoids have been found to suppress carcinogenesis in a variety of animal models and in a few clinical trials with individuals at high risk for developing cancer. Their use in future long-term prevention trials and their eventual application in chemoprevention regiments will require strategies to decrease side effects of existing retinoids or the identification of more effective retinoids with few or no side effects. Combination with other chemopreventive agents may also enhance the clinical
Reviewers
Dr. Franca Formelli, Chemoprevention Unit, Department of Experimental Oncology, Instituto Nazionale Tumori, Via Venezian 1, I – 20133 Milano, Italy.
Luigi M. De Luca, Ph.D., Chief, Differentiation Control Section, LCCTP, DBS, National Cancer Institute, Building 37, Room 3A-17, Bethesda, MD 20892-4255, USA.
Dr. Anton M. Jetten, Deputy Chief LPP, Head Cell Biology Section, NIEHS, National Cancer Institute, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
Shi-Yong Sun, Ph.D. 1990, Ph.D., Peking Union Medical College/Chinese Academy of Medical Sciences, Beijing, People's Republic of China; 1994–1997, Postdoctoral Fellow, The University of Texas M.D. Anderson Cancer Center, Houston, USA; 1997–1999, Research Associate, The University of Texas M.D. Anderson Cancer Center; 1999 to present, Assistant Professor, The University of Texas M.D. Anderson Cancer Center.
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Shi-Yong Sun, Ph.D. 1990, Ph.D., Peking Union Medical College/Chinese Academy of Medical Sciences, Beijing, People's Republic of China; 1994–1997, Postdoctoral Fellow, The University of Texas M.D. Anderson Cancer Center, Houston, USA; 1997–1999, Research Associate, The University of Texas M.D. Anderson Cancer Center; 1999 to present, Assistant Professor, The University of Texas M.D. Anderson Cancer Center.
Reuben Lotan, Ph.D. 1976, Ph.D., the Weizmann Institute of Science, Rehovot, Israel; 1976–1978, post-doctoral training, the Salk Institute, San Diego CA, USA; 1978–1980, Assistant Professor (visiting), University of california, irvine CA, USA; 1980–1984, Senior Scientist, the Weizmann Institute of Science; 1984–1988, Associate Professor, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 1988-present, Professor, The University of Texas M.D. Anderson Cancer Center; 1997-present, Irving and Nadine Mansfield and Robert David Levitt Cancer Research Chair, The University of Texas M.D. Anderson Cancer Center; 1994 to present, Associate Vice President for Cancer Prevention, The University of Texas M.D. Anderson Cancer Center.