Nutrition Volume 16, Numbers 7/8, 2000
Vitamin A and Cancer
11. Giuliano AR, Papenfuss M, Nour M, et al. Antioxidant nutrients: associations
with persistent human papillomavirus infection. Cancer Epidemiol Biomark Prev
1997;8:917
12. Potischman N, Brinton LA. Nutrition and cervical dysplasia. Cancer Causes
Control 1996;7:113
13. Basu J, Palan PR, Vermund SH, et al. Plasma ascorbic acid and ␤-carotene levels
in women evaluated for HPV infection, smoking, and cervical dysplasia. Cancer
Det Prev 1991;15:167
14. Potischman N, Herrero R, Brinton LA, et al. A case-control study of nutrient
status and invasive cervical cancer. Am J Epidemiol 1991;134:1347
15. Potischman N, Hoover R, Brinton LA, et al. The relations between cervical
cancer and serological markers of nutritional status. Nutr Cancer 1994;21:193
16. Van Eenwyk J, Davis F, Bowen P. Dietary and serum carotenoids and cervical
intraepithelial neoplasia. Int J Cancer 1991;48:34
17. Palan P, Mikhail M, Goldberg G, et al. Plasma levels if ␤-carotene, lycopene,
canthaxanthin, retinol, ␣-tocopherol in cervical intraepithelial neoplasia and
cancer. Clin Cancer Res 1996;2:181
18. Batieha AM, Armenian HK, Morris JS, Spate VE, Comstock GW. Serum
micronutrients and the subsequent risk of cervical cancer in a population based
nested case-control study. Cancer Epidemiol Biomark Prev 1993;2:335
19. Clinton SK, Emenhiser C, Schwartz SJ, et al. Cis-trans lycopene isomers,
carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomark Prev
1996;5:823
20. Mangels AR, Holden JM, Beecher GR, Froman M, Lanza E. Carotenoid content
of fruits and vegetables: an evaluation of analytic data. J Am Diet Assoc
1993;93:284
21. Brock K, Berry G, Mock P, et al. Nutrients in diet and plasma and risk of in situ
cervical cancer. J Natl Cancer Inst 1988;80:580
22. Palan P, Mikhail M, Basu J, Romney S. Plasma levels of antioxidant ␤-carotene
and ␣-tocopherol in uterine cervix dysplasia and cancer. Nutr Cancer 1991;15:13
23. Knekt P. Serum vitamin E level and risk of female cancers. Int J Epidemiol
1988;17:281
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24. Cuzick J, de Stvola B, Russel M, Thomas B. Vitamin A, vitamin E, and the risk
of cervical intraepithelial neoplasia. Br J Cancer 1990;62:651
25. Kwasniewska A, Tukendorf A, Semczuk M. Content of ␣-tocopehrol in blood
serum of human papillomavirus-infected women with cervical dysplasias. Nutr
Cancer 1997;28:248
26. Giuliano AR, Gapstur S. Can cervical dysplasia and cancer be prevented with
nutrients? Nut Rev 1998;56:9
27. Palmer HJ, Paulson KE. Reactive oxygen species and antioxidants in signal
transduction and gene expression. Nutr Rev 1997;55:353
28. Beck MA, Shi Q, Morris VC, Levander OA. Rapid genomic evolution of a
non-virulent Coxsackievirus B3 in selenium-deficient mice results in selection of
identical virulent isolates. Nat Med 1995;1:433
29. Peterhans E. Oxidants and antioxidants in viral diseases: disease mechanisms and
metabolic regulation. J Nutr 1997;127:962S
30. Hennet T, Perhans E, Stocker R. Alterations in antioxidant defenses in lung and
liver of mice infected with influenza-A virus. J Gen Virol 1992;73:39
31. Oda T, Akaike T, Hamamoto T, et al. Oxygen radicals in influenza-induced
pathogenesis and treatment with pyran polymer-conjugated SOD. Science 1989;
244:974
32. Pace GW, Leaf CD. The role of oxidative stress in HIV disease. Free Rad Biol
Med 1995;19:523
33. Packer L, Suzuki YJ. Vitamin E and alpha-lipoate: role in antioxidant recycling
and activation of the NF-␬B transcription factor. Mol Aspects Med 1993;14:229
34. Cripe TP, Alderborn A, Anderson RD, et al. Transcriptional activation of the
human papillomavirus-16 P97 promoter by an 88-nucleotide enhancer containing
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35. Offord EA, Beard P. A member of the activator protein 1 family found in
keratinocytes but not in fibroblasts required for transcription from a human
papillomavirus type 18 promoter. J Virol 1990;64:4792
36. Rosl F, Das BC, Lengert M, Geletneky K, zur Hausen H. Antioxidant-induced
changes of the AP-1 transcription complex are paralleled by a selective suppression of human papillomavirus transcription. J Virol 1997;71:362
Vitamin A and Cancer
Richard M. Niles, PhD
From the Department of Biochemistry and Molecular Biology, Marshall University School
of Medicine, Huntington, West Virginia, USA
HISTORICAL PERSPECTIVE OF VITAMIN A AND
CANCER (TABLE I)
The connection between vitamin A and development of cancer was
made rather soon after the discovery of this vitamin and its
chemical structure. Wolbach and Howe’s pioneering studies in
1925 showed that vitamin-A deficiency inhibited proliferation and
differentiation of epithelial cells.1 During the next several decades,
emphasis was placed on elucidating the chemical structure of
vitamin A and studying its metabolism. In the late 1950s and
through the 1960s, a number of reports demonstrated that
vitamin-A deficiency induced an increase in the number of spontaneous and chemically induced tumors in animals.2– 4 These findings were followed by studies that demonstrated that “pharmacologic” concentrations of vitamin A added to the diet decreased the
incidence of chemically induced tumor in animals.5–7 During this
period, much effort was made to determine the physiologic metabolites of vitamin A and how vitamin A was processed and
circulated through the organism.8 These studies revealed the key
role of the liver in storing and processing vitamin A for transport
Correspondence to: Richard M. Niles, PhD, Department of Biochemistry
and Molecular Biology, Marshall University School of Medicine, 1542
Spring Valley Drive, Huntington, WV 25704, USA. E-mail: niles@
marshall.edu
throughout the circulatory system.9,10 Evidence from these studies
suggested that vitamin-A acid (retinoic acid) is the major physiologically active retinoid. Retinol circulates as a complex with
plasma retinol-binding protein and transthyreitin (prealbumin). It
is taken up by cells and bound within these cells by cellular
retinol-binding protein. The cellular retinol-binding protein then
delivers retinol to intracellular sites, where it is converted to
retinoic acid.
A key observation was made by Strickland and Mahdavi11 who
demonstrated that retinoic acid could induce the differentiation of
teratocarcinoma cells in vitro and in vivo. Also during this period,
Lotan and Nicholson12 established that retinoic acid inhibited the
growth of many “normal” transformed and tumor cells in culture.
The initial discovery that retinoic acid could induce the differentiation of malignant leukemia cells was reported by Breitman et
al.13 In addition to these findings, the same group found that
retinoic acid could induce the differentiation of fresh leukemic
cells from patients with promyelocytic leukemia into mature granulocytes.14 Despite the extraordinary promise of these findings by
a research team at the National Institutes of Health, this basic
research was not translated into clinical trials until 1988, when
Huang et al.15 reported a series of successful clinical trials using
retinoic acid to treat patients with promyelocytic leukemia. After
replication of Huang et al.’s results by investigators in France,16
clinical trials were finally conducted in the United States that
verified the findings reported in the other studies.17
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Niles
Nutrition Volume 16, Numbers 7/8, 2000
TABLE I.
MAJOR 20TH-CENTURY MILESTONES IN RESEARCH ON
VITAMIN A AND CANCER
1925
1950–1960
1960–1970
1977
1978
1980–1981
1987
1988
1993
1992
1998
Wolbach and Howe first describe the effect of vitamin-A
deficiency on the proliferation and differentiation of
epithelial cells
Various investigators demonstrate that vitamin-A
deficiency induces an increase in the number of
spontaneous and chemically induced tumors in
animals
A variety of studies report that exogenously added
retinoids can suppress the incidence of chemically
induced tumors in animals
Lotan and Nicholson demonstrate that retinoids inhibit
the growth of many “normal” transformed and tumor
cells in culture
Strickland and Mahdavi report that retinoic acid induces
differentiation of teratocarcinoma cells grown in tissue
culture
Breitman et al. find that retinoid acid induces the
differentiation of the HL-60 human leukemic cells and
also cells from patients with promyelocytic leukemia;
these basic research findings form the basis of future
clinical treatment of this disease with retinoids
The discovery of nuclear retinoic-acid receptors is
reported independently by Giguerre et al. and by
Petkovitch et al.
Huang et al. report the successful use of retinoic acid to
treat patients with acute promyelocytic leukemia
Lippman et al. report that retinoids significantly decrease
the incidence of second primary tumors in patients
with head-and-neck cancer
Coactivators and corepressors for RAR are reported by
different investigators
Bischoff et al. report that targretin, an RXR-selective
retinoid, causes complete remission of mannary cancer
in rats
During this period (between 1985 and 1995), various clinical
trials were conducted to determine the efficacy of retinoic acid in
inducing remissions in a variety of solid tumors. Most of these
studies reported that retinoic acid (usually 13-cis) had little or no
ability to induce an objective response.18 One exception was the
study by Lippman et al.19 who reported that retinoic acid significantly decreased the incidence of second primary tumors in patients with head-and-neck cancer who had their first primary tumor
surgically removed. It did not have any significant effect on the
progression or recurrence of the first primary tumor. Thus, it
appears that, in this instance, retinoic acid acts as a chemopreventive agent rather than as a chemotherapeutic agent.
It has been known since the mid-1970s that retinoic acid
specifically altered gene expression in target tissues. The major
problem was deciphering how retinoic acid accomplished this task.
Several reports suggested that cellular retinoic-acid– binding protein may translocate into the nucleus and mediate the effect of
retinoic acid on gene expression.20 Although this idea fell out of
favor, recent published articles establish that the type-II cellular
retinoic-acid– binding protein is indeed present in the nucleus and
can enhance the effect of retinoic acid on regulating target gene
expression.21,22 A major advance in the understanding of how
retinoic acid might inhibit cancer development and progression
occurred in 1987 when Giguere et al.23 and Petkovich et al.24
reported the discovery of nuclear receptors for retinoic acid. These
receptors were found to contain the same structural modules as the
FIG. 1. Schematic diagram of the assembly of a transcriptionally active
RXR:RAR complex on target genes. (A) Inactive RXR:RAR complex
bound to corepressor. The RXR ligand-binding site is sterically blocked by
RAR. Corepressor has histone deacetylase activity, which keeps the chromatin in the “condensed” state. (B) Assembly of active complex. Addition
of the ligand all-trans–retinoic acid, delivered to the nucleus by CRABP II,
induces a conformational change in RAR. As a result of the change, the
corepressor is released, the RXR is free to bind its ligand 9-cis–retinoic
acid, and coactivators such as CBP/p300, pCAF, and others (e.g., steroid
coactivator-1 [SRC-1]) bind to the RXR and RAR. CBP/p300 and pCAF
have histone-acetyltransferase activity that induces a “loose” state of
chromatin structure required for active gene transcription.
family of steroid hormone receptors. Additional studies showed
that there is a family of retinoic-acid nuclear receptors. One class
of receptors (RAR␣, ␤, and ␥) bind all-trans and 9-cis-retinoic
acid,25,26 whereas the other class of receptors (RXR ␣, ␤, and ␥)
bind only 9-cis-retinoic acid with high affinity.27,28 It was also
determined that the RXR formed heterodimers with a number of
other nuclear receptors such as RAR, vitamin-D3 receptor,
thyroid-hormone receptor, and peroxisomal-proliferator–activator
receptor.29,30 Under physiologic conditions, only the RXR:RAR
heterodimer leads to productive DNA binding.31
Between 1992 and 1995, it was discovered that coactivator and
corepressor proteins also regulated the activity of the RAR and
RXR.32,33 The corepressors bind to the receptors in the absence of
ligand and prevent it from activating transcription of the target
genes. In contrast, coactivators bind to the receptors only when
ligand is bound to the receptor, and they enhance the activation of
transcription. One of the coactivators, CBP/p300, acts to enhance
the activity of a plethora of transcription factors.34 CBP and a
companion protein, pCAF, contain histone acetyltransferase activity.35 Recently, it was shown that some corepressors contain histone deacetylase activity.36 –38 Thus, a current hypothesis is that
some of these cofactors serve to remodel chromatin and thus alter
the accessibility of the receptor to DNA. Our current model of how
the complex of RXR:RAR and cofactors regulate retinoic-acid–
induced gene expression is shown in Figure 1.
Nutrition Volume 16, Numbers 7/8, 2000
A significant amount of data suggest that RAR␤ may be a
tumor-suppressor gene because its expression is lost in a variety of
tumors.39,40 Further, induction of RAR␤ expression invariably
accompanies the growth inhibition and stimulation of differentiation of tumor cells by retinoic acid.41– 43 However, mutations in
some of the cofactors required for RAR:RXR activity could also
lead to loss of retinoic-acid control of gene expression. Because
some of the coactivators needed for optimal RAR activity are also
required by other nuclear receptors and transcription factors, the
stoichiometry of all these different molecules will determine the
intensity of the response to retinoic acid. In other words, the
relative amounts of the RARs and RXRs and their ability to
compete for coactivators will influence the ability of retinoic acid
to control the physiologic functions of cells.
One of the problems with using retinoic acid as a therapeutic
agent is that at pharmacologic concentrations it has a number of
potential side effects such as liver toxicity, central nervous system
toxicity, and elevation of serum triacylglycerols. These side effects
are thought to be due to the ability of all-trans–retinoic acid to bind
and activate all of the different RARs. There has been a concerted
effort in recent years to develop receptor-selective retinoids.44,45
Currently, there are a variety of retinoid analogs that have relatively good RAR-selective agonist or antagonist activity. It should
be emphasized that there are no absolutely specific RAR-subtype
retinoids. When used at high concentrations, these compounds will
bind and activate other retinoid receptors. This could present a
problem in clinical settings, where there may be a need to use
higher concentrations of the retinoid. Therefore, it was encouraging to learn of the recent work of Bischoff et al. who found that
targretin, an RXR-selective retinoid, caused complete remission of
mammary cancer in rats.46 There are also reports that RARselective retinoids can overcome the retinoid resistance found in
cases of promyelocytic leukemia that have become refractory to
treatment with retinoic acid.47 These studies suggest retinoids with
receptor-subtype selectivity may have therapeutic usefulness in the
prevention and treatment of certain types of cancer.
FUTURE PREDICTIONS AND AREAS IN NEED OF
EXPLORATION (TABLE II)
Substantial progress has been made during the last 20 y in advancing our knowledge of how retinoids achieve their biologic effects
and in turn how they may be involved in the prevention and
treatment of cancer. Although some epidemiologic studies have
suggested that there may be a correlation between low dietary
vitamin-A intake and development of certain cancers, molecular
studies have indicated that defects in the retinoid-signaling pathway likely contribute to the development of many types of cancers.
In particular, a significant amount of experimental data supports
the hypothesis that RAR␤ may function as a tumor-suppressor
gene. Expression of RAR␤ in tumor cells not expressing this gene
restores retinoid-induced growth inhibition and apoptosis.41– 43
Transgenic mice in which RAR␤ gene expression is downregulated have an increased incidence of lung cancer.48 Decreased
RAR␤ expression also appears to be responsible for a lack of
antitumor activity of retinoids in animals.49 Deletion of the short
arm of chromosome 3p24, a region containing the RAR␤ gene,
occurs with high frequency in human tumors.50 Also, a variety of
tumors have a high frequency of abnormal expression of the
RAR␤ gene but not of the genes encoding the other RAR
subtypes.51–53 In light of the data already accumulated, it is likely
that within the next decade the tumor-suppressor hypothesis will
be proven correct and that RAR␤ will become the target of
therapeutic strategies.
To develop these therapeutics, we need a better understanding
of retinoid-receptor biology. A variety of proteins that interact with
these nuclear retinoid receptors have been discovered in the past
Vitamin A and Cancer
575
TABLE II.
IMPORTANT QUESTIONS FOR RETINOIDS AND CANCER
BIOLOGY IN THE 21ST CENTURY
Does RAR␤ function as a tumor suppressor gene?
How does the complex of nuclear retinoid receptors and coactivators
result in stimulation of target gene expression?
What is the role of phosphorylation and protein stability in the
regulation of nuclear retinoid-receptor function?
How is the production of intracellular retinoic acid regulated and how is
it delivered to the nuclear receptors. Is this process altered in cancer
cells?
What are the pathways by which retinoids regulate proliferation,
apoptosis, and differentiation? What is the identity of the primary and
downstream target genes? Are these retinoid-regulated pathways
deranged in cancer cells?
few years. It is not clear how all of the proteins assemble into a
complex to activate transcription of target genes. Some of these
coactivators and corepressors appear to be ubiquitously expressed,
whereas others show tissue-specific expression. Tissue-specific
expression of coactivators is intriguing because it suggests that
they may control tissue-specific retinoid-regulated gene expression. In addition to proteins that bind and modulate the activity of
these receptors, the nuclear retinoid receptors can be regulated at
the level of synthesis (cyclic AMP can either induce or repress
RAR expression, depending on the cell type54 –56) and through
phosphorylation. Quite recently, it was discovered that the RARs
are degraded through the ubiquitination–proteasome pathway and
that their degradation can be accelerated by ligand binding.57
Because the affinity of the RAR for retinoic acid is so strong,
accelerated degradation of the ligand-bound receptor provides a
means for turning off the induction of target gene transcription that
is independent of ligand disassociation. Because there are so many
ways by which the activity of the nuclear retinoid receptors can be
regulated, it will take a considerable amount of time before we
fully understand how nuclear retinoid receptors function in vivo
under different physiologic scenarios.
A fundamental question, still unanswered, is the exact pathway
(enzymes or subcellular localization) by which retinol is taken up
by cells, converted to all-trans–retinoic acid or 9-cis–retinoic acid
and then delivered to the nuclear retinoid receptors. Indeed, in light
of the very-low cellular concentration of 9-cis–retinoic acid, there
is some lingering doubt that this retinoid is the natural ligand for
RXR. The recent, unexpected, finding that CRABP II is found in
the nucleus, binds to RAR, and stimulates its transcriptional activity22 provides a potential pathway for nuclear delivery of this
retinoid. It is likely that these pathways for regulating ligand
availability and for the regulation of nuclear retinoid-receptor
function will also be disrupted in some cancers.
The exact pathway(s) by which retinoids control proliferation,
apoptosis, and differentiation remains a mystery. It is likely that
different pathways, i.e., different sets of genes, will be used by
different cell types. The use of DNA microarrays, by which one
can examine changes in the expression of thousands of genes in
one experiment, will provide abundant data regarding which genes
are directly regulated by retinoids, whose activation in turn regulates downstream target genes, ultimately leading to the biologic
response. It is likely that in the next 20 y these retinoid-regulated
pathways will be mapped in a variety of cell types. This information will provide additional insight into how alterations in the
retinoid-signaling pathway might contribute to carcinogenesis and
yield target identification for the development of new molecularbased therapies for the treatment of cancer.
576
Niles
Nutrition Volume 16, Numbers 7/8, 2000
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