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Department of Pathophysiology, and
* Center for Laboratory Animal Care, University of Vienna Medical School, Austria;
Institute for Preventive Medicine, Nutrition and Cancer, and Division of Clinical Chemistry, University of Helsinki, Finland; and
** Geriatric Research, Education, and Clinical Center, St. Louis Veterans Administration Medical Center, St. Louis, MO 63125
3 To whom correspondence should be addressed. E-mail: Heide.Cross{at}akh-wien.ac.at.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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-hydroxylase) and catabolism (CYP24; 1,25-D3–24-hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of CYP27B1, vitamin D receptor, and estrogen receptor-ß (the high-affinity receptor for phytoestrogens) are enhanced early during human colorectal cancer, which suggests an interactive physiological defense against tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of CYP27B1 and of CYP24 by genistein at 0.05–50 µmol/L. The high concentration of 50 µmol/L is very effective in eliminating CYP24 expression in prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively genistein feeding, elevates CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional calcium, CYP24 rises in parallel to enhanced colonic proliferation, and genistein counteracts both. We suggest that nutritional soy or genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of tumor progression.
KEY WORDS: • extrarenal vitamin D synthesis • extrarenal vitamin D catabolism • estrogen receptor-ß • genistein • tumor prevention
Cholecalciferol (vitamin D-3) is nutritionally provided mainly in oily fish or fortified foods. However, a major part is synthesized in the skin by ultraviolet (sun) energy, and this is of particular relevance in countries at southern latitudes. Vitamin D-3 is the precursor of the active hormonal metabolite 1,25-dihydroxyvitamin D3 (1,25-D3),4 which has an at least 1000-fold higher activity than the precursor with respect to many physiological functions. 1,25-D3 is endogenously synthesized by 25-hydroxylation in the liver by the cytochrome P450 enzyme CYP27A1 and by 1-hydroxylation (by CYP27B1) in the kidney. When sufficient 1,25-D3 has been generated, catabolic pathways take over and 24-hydroxylation (by CYP24) is activated. The hormone exerts its genomic effects by binding to the vitamin D receptor, which then acts as a transcription factor.
Adequate levels of 1,25-D3 are not only necessary to maintain human serum calcium homeostasis and normal bone mineralization but may also provide some protection against cancer risk. Epidemiologic studies have demonstrated an inverse correlation between risk of several cancers and sun exposure, dietary fish consumption, and serum levels of 25-D3 (1). Serum concentrations of 1,25-D3, however, did not correlate with disease incidence. This may be because although serum picomolar concentrations of 1,25-D3 may be sufficient to maintain calcium homeostasis, these concentrations are not adequate for control of tumor cell growth. Numerous previous studies demonstrated the relevance of pharmacological doses of 1,25-D3 and vitamin D analogs in preventing tumor formation and inducing differentiation and apoptosis in colon, prostate, and mammary cells (2–4). However, at such doses in vivo, hypercalcemic effects frequently occur, precluding treatment of tumor patients.
Only recently another rather unexpected physiological link between vitamin D and cancer prevention and therapy has been observed that could be of great relevance for reduction of solid tumor incidence. In addition to renal production of the active steroid hormone, a variety of cell types in different tissues were also shown to be able to synthesize 1,25-D3 from its precursor 25-D3 and, importantly, to catabolize the hormone. Thus, colonocytes in culture have a high capacity for synthesizing 1,25-D3 because 5–10% of the precursor 25-D3 is converted to the active metabolite (5). A wide spectrum of vitamin D metabolites has been detected in freshly isolated colon tumor cells (6). Increasing levels of CYP27B1 and vitamin D receptor mRNA are detected during early human colon tumor progression whereas expression is greatly diminished during late-stage high-grade cancer. In contrast, expression is exceedingly low in colon crypts of patients without cancer (7,8). Several laboratories detected the presence of CYP27B1 and also CYP24 in normal and malignant prostate (9) and mammary cells (10). This suggested a potentially protective autocrine and paracrine action of 1,25-D3 synthesized in tumor cells while high or aberrant expression of CYP24 at the tumor site (6) could cause rapid catabolism of 1,25-D3 into less active vitamin D compounds. In this respect it is of interest that CYP24 was recently suggested to be a potential oncogene (11).
Our data from human colorectal tumors suggested to us a new concept for tumor prevention and also for cancer patient therapy: to increase availability of 1,25-D3 at the tumor site by regulating extrarenal vitamin D metabolic enzymes. This prompted us to find factors that could control synthesis of 1,25-D3 (i.e., expression level of CYP27B1) and catabolism of 1,25-D3 (i.e., expression level of CYP24).
Sex hormones and tumor occurrence
Considerable physiological evidence is accumulating for a protective effect of estrogenic substances against colorectal cancer incidence, although sex hormones are generally known to support occurrence of malignancies in hormone-dependent cancers such as those of the breast and prostate. Women of all ages are less likely than men to develop colon cancer (Fig. 1A), and postmenopausal hormone replacement therapy reduces even further colon cancer risk by up to 30%. In an extensive study, Potter et al. (13) demonstrated a lower risk of adenomatous polyps of the large bowel with hormone replacement therapy. In addition, in several rat models for colon cancer, males were shown to have higher tumor and aberrant crypt formation rates (14,15), the latter being a typical precursor lesion of colorectal cancer. Notably, a large comprehensive study by the Women’s Health Initiative investigators (16) of physiological effects of hormone replacement therapy was stopped because most variables that were assumed to be beneficially affected by hormone replacement therapy were either negatively affected (coronary heart disease, stroke, invasive breast cancer) or not affected (pulmonary embolism). Highly significant exceptions were a reduction in the incidence of colorectal cancer and osteoporosis.
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and ß are involved. In human colorectal tumors, both in males and females, the ER-ß subtype is much more abundant than the ER- (our unpublished observations). As a result, ER-ß activation by estrogens could be transduced into antimitogenic pathways, as was observed in breast cancer cells (17). Another mechanism of action could conceivably involve modulation of CYP27B1 and CYP24 expression by estrogens at extrarenal locations, which could result in enhanced local synthesis of 1,25-D3, the antimitotic prodifferentiating active metabolite of vitamin D. Soy consumption and cancer incidence
Reduced incidence, especially of hormone-related cancers such as mammary and prostate tumors and also of colon tumors, has been linked to the consumption of a typical Asian diet. Figure 1 demonstrates incidence and death rates of colon, breast, and prostate cancer in the United States and Japan. Although cancer incidence in women is much lower than in men in both countries, there is also a difference when the 2 countries are compared. Japanese men as well as women have lower colorectal cancer incidence than their American counterparts although mortality is quite similar when related to specific incidence data. In hormone-dependent cancers such as those of the breast and prostate, incidence is exceedingly low in Japan (and was even lower in earlier decades) compared with that in United States. Mortality, again in proportion to incidence, is rather similar. Numerous reports have suggested that this difference in tumor incidence is probably due to consumption of soy as staple food in Asian countries in contrast to Western industrialized countries. Among other components, soy contains large amounts of phytoestrogens. These substances, through their potential to act as selective estrogen receptor modulators, may affect vitamin D–related inhibition of tumor growth by upregulating extrarenal synthesis of 1,25-D3. Genistein, the most prominent phytoestrogen in soy, is known to regulate other P450 enzymes, such as 5-reductase and 17ß-hydroxysteroid dehydrogenase, which are essential for metabolism of sex hormones.
Effect of soy and genistein on expression of CYP27B1 and CYP24 in the mouse colon may depend on the proliferative status of cells
We previously demonstrated the effects of soy feeding (20% soybean meal for 3 mo) on CYP24 expression in mouse colon (18). Although we observed a reduction of expression, interindividual variations were high, similar to those observed for intrinsic proliferation of colonic crypts in different individuals. This suggested to us that interindividual variations in CYP24 expression may be related to proliferation and that a well-defined suppression of CYP24 expression by soy could best be observed in mouse colon crypt cells stimulated to proliferate.
When mice were fed a normal level of calcium in their diet (0.9%), the expression level of proliferating cell nuclear antigen (PCNA), a marker for the proliferation of crypt cells, was relatively low and, when evaluated immunohistochemically, only the lower third of crypt cells were positive (Fig. 2A). When mice were fed 0.04% calcium in their diet, PCNA expression extended well into the upper 50% of the crypt (Fig. 2B). Although feeding 20% soybean meal to animals on the 0.9% calcium diet did not change the expression of PCNA dramatically (not shown), mice on the low-calcium diet with an additional 20% soybean meal demonstrated a reversion of the initially high PCNA expression to normal low levels (Fig. 2C).
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-hydroxylation and, at the same time, to suppress C24 oxidation and subsequent side chain cleavage. Therefore, phytoestrogens could allow colonocytes to maintain a high intrinsic level of antimitotically active 1,25-D3. Estrogen receptor expression
It is well accepted that ER- and ER-ß show a distinct tissue-specific distribution pattern and that both subtypes are expressed during human tumorigenesis (23). Foley et al. (24) suggested that malignant transformation of the human colon is associated with a marked diminution of ER-ß expression, which is widely regarded to be the predominant ER subtype in normal human colonic tissue (25,26). The 2 ER subtypes show little or no homology between their ligand-binding and N-terminal transactivation (AF-1) domains (27). This seems to be why ER- and ER-ß have opposite effects on gene expression (28). For example, estrogenic compounds stimulate proliferation of human breast cancer cells by engaging the ER-(29) whereas proliferation is suppressed by signaling via ER-ß(17).
We evaluated ER- and ER-ß expression in the colon of mice fed a diet containing 20% soy protein for 3 mo. Evaluation of ER expression by immunoblotting demonstrated that ER- expression in colonocytes is indeed much lower than that of ER-ß. However, neither receptor expression was at all affected by soy feeding (Fig. 5).
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In this in vitro study we used the well-known prostate cancer cell line DU-145, which is androgen receptor negative, and the breast cancer cell line MCF-7. A comparison of these cell lines with respect to reactivity to genistein was considered highly interesting because DU-145 cells almost exclusively contain ER-ß whereas MCF-7 cells primarily contain ER-, as demonstrated by reverse-transcriptase (RT)-PCR in Figure 6.
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The frequently observed inverse correlation between low serum levels of 25-D3 and a variety of human tumor incidences hints at the importance of the vitamin D precursor for tumor prevention. We suggest that the amount of serum 25-D3 as the source of adequate extrarenal, tissue-located synthesis of 1,25-D3 as well as the extrarenal expression level of vitamin D hydroxylases may play a crucial role in this important physiological mechanism. Although it has become increasingly apparent that exogenous application of 1,25-D3 or of vitamin D analogs in cancer therapy is not feasible because of hypercalcemic effects, 1,25-D3 synthesis in tumor tissues could conceivably result in very localized high concentrations resulting in tumor-preventive antimitotic, proapoptotic activity without significantly altering serum concentrations of the steroid hormone. Optimal regulation of extrarenal vitamin D hydroxylases would be a prerequisite for high accumulation.
Our data demonstrate that nutritional soy could indeed regulate synthesis and catabolism of 1,25-D3 in the colon in such a manner that increased levels of the steroid hormone synthesized in colonic tissue would be available. It is striking that this mechanism could become primarily activated by nutritional soy under hyperproliferative conditions in the colon. Indeed, such a mechanism could be considered a perfect example of nutritional prevention of tumor progression that is most effective under premalignant conditions. The major phytoestrogen in soy, genistein, is very effective in regulating 1,25-D3 synthesis even after a single application under nonproliferative colonic conditions. This suggests that genistein may be the metabolite in dietary soy that regulates vitamin D synthesis in the colon.
Our results in vivo and in vitro do not necessarily support the concept of signal transduction of phytoestrogens via ER-ß. The biphasic response in DU-145 prostate cells (which mainly express ER-ß) to genistein, where low concentrations increase and high concentrations substantially decrease the capacity of cells to synthesize 1,25-D3, points to dual mechanisms. Although lower doses may mediate effects via ER-ß, other molecular targets such as tyrosine kinases are affected only at much higher doses of genistein. This, in turn, could modulate tumor cell growth (32) that could affect vitamin D hydroxylase expression.
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FOOTNOTES |
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2 This work was supported by the World Cancer Research Fund (to H.S.C.), 2 grants from the Austrian National Bank Nr. 9850 (to H.S.C.) and Nr. 9335 (to E.K.), a grant from the Sigrid Juselius Foundation, Helsinki, Finland (to H.A.), and a grant from the U.S. Department of Veteran Affairs (to H.J.A.).
4 Abbreviations used: 1,25-D3, 1,25-dihydroxyvitamin D3; ER, estrogen receptor; PCNA, proliferating cell nuclear antigen.
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