Retinoids and their receptors in cancer development and chemoprevention

https://doi.org/10.1016/S1040-8428(01)00144-5Get rights and content

Abstract

Retinoids play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially epithelial cells, mainly through interaction with two types of nuclear receptors: retinoic acid receptors (RARα, β and γ) and retinoid X receptors (RXRα, β and γ). Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens. This is in agreement with the epidemiological studies indicating that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer. At the molecular level, aberrant expression and function of nuclear retinoid receptors have been found in various types of cancer including premalignant lesions. Thus, aberrations in retinoid signaling are early events in carcinogenesis. Retinoids at pharmacological doses exhibit a variety of effects associated with cancer prevention. They suppress transformation of cells in vitro, inhibit carcinogenesis in various organs in animal models, reduce premalignant human epithelial lesions and prevent second primary tumors following curative therapy for epithelial malignancies such as head and neck, lung, liver, and breast cancer.

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.

References (123)

  • R.J Lin et al.

    Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers

    Mol Cell

    (2000)
  • S Minucci et al.

    Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation

    Mol Cell

    (2000)
  • H Qiu et al.

    Loss of retinoic acid receptor-beta expression is an early event during esophageal carcinogenesis

    Am J Pathol

    (1999)
  • K.A Robertson et al.

    Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity

    Blood

    (1992)
  • S.L Costa et al.

    Dominant negative mutant of retinoic acid receptor alpha inhibits retinoic acid-induced P19 cell differentiation by binding to DNA

    Exp Cell Res

    (1996)
  • F.A.E Kruyt et al.

    Transcriptional regulation of retinoic acid receptor β in retinoic acid-sensitive and -resistant P19 embryocarcinoma cells

    Mech Dev

    (1991)
  • A.K Verma et al.

    Expression of retinoic acid nuclear receptors and tissue transglutaminase is altered in various tissues of rats fed a vitamin A-deficient diet

    J Nutr

    (1992)
  • H Hennings et al.

    Retinoic acid promotion of papilloma formation in mouse skin

    Cancer Lett

    (1982)
  • D Moglia et al.

    Effects of topical treatment with fenretinide (4-HPR) and plasma vitamin A levels in patients with actinic keratoses

    Cancer Lett

    (1996)
  • R Sankaranarayanan et al.

    Chemoprevention of oral leukoplakia with vitamin A and beta carotene: an assessment

    Oral Oncol

    (1997)
  • J Han

    Highlights of the cancer chemoprevention studies in China

    Prev Med

    (1993)
  • M Sporn et al.

    Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids)

    Federation Proc

    (1976)
  • L.J Gudas et al.

    Cellular biology and biochemistry of the retinoids

  • L.M DeLuca

    Retinoids and their receptors in differentiation, embryogenesis and neoplasia

    FASEB J

    (1991)
  • R Lotan

    Retinoid and apoptosis: implication for cancer chemoprevention and therapy

    J Natl Cancer Inst

    (1995)
  • L Nagy et al.

    Retinoid-induced apoptosis in normal and neoplastic tissues

    Cell Death Differ

    (1998)
  • L.A Hansen et al.

    Retinoids in chemoprevention and differentiation therapy

    Carcinogenesis

    (2000)
  • R Lotan

    Retinoids in cancer chemoprevention

    FASEB

    (1996)
  • R.C Moon et al.

    Retinoids and cancer in experimental animals

  • W.K Hong et al.

    Retinoids and human cancer

  • P Chambon

    A decade of molecular biology of retinoic acid receptors

    FASEB J

    (1996)
  • D.J Mangelsdorf et al.

    The retinoid receptors

  • L Alland et al.

    Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression

    Nature

    (1997)
  • T Heinzel et al.

    A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression

    Nature

    (1997)
  • N.L Lill et al.

    Binding and modulation of p53 by p300/CBP coactivators

    Nature

    (1997)
  • B Blumberg et al.

    Orphan nuclear receptors – new ligands and new possibilities

    Genes Dev

    (1998)
  • S.B Wolbach et al.

    Tissue changes following deprivation of fat-soluble vitamin A

    J Exp Med

    (1925)
  • I Lasnitzki

    Reversal of methylcholanthrene-induced changes in mouse prostates in vitro by retinoic acid and its analogues

    Br J Cancer

    (1976)
  • E Bjelke

    Dietary vitamin A and human lung cancer

    Int J Cancer

    (1975)
  • H de The

    Altered retinoic acid receptors

    FASEB J

    (1996)
  • C Arnould et al.

    The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia

    Hum Mol Genet

    (1999)
  • L.Z He et al.

    In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications

    Oncogene

    (1999)
  • X.C Xu et al.

    Aberrant expression and function of retinoid receptors in cancer

  • X.C Xu et al.

    Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues

    Cancer Res

    (1994)
  • R Lotan et al.

    Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin

    N Engl J Med

    (1995)
  • X.C Xu et al.

    Suppression of retinoic acid receptor beta in non-small-cell lung cancer in vivo: implications for lung cancer development

    J Natl Cancer Inst

    (1997)
  • L Castillo et al.

    Analysis of retinoic acid receptor beta expression in normal and malignant laryngeal mucosa by a sensitive and routineapplicable reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay method

    Clin Cancer Res

    (1997)
  • E Picard et al.

    Expression of retinoid receptor genes and proteins in non-small-cell lung cancer

    J Natl Cancer Inst

    (1999)
  • B Houle et al.

    Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells

    Proc Natl Acad Sci USA

    (1993)
  • J Berard et al.

    Lung tumors in mice expressing an antisense RARbeta2 transgene

    FASEB J

    (1996)
  • Cited by (302)

    View all citing articles on Scopus

    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.

    View full text