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Endocrinology |
, Retinoid X Receptor 
, and all-trans Retinoic Acid Than Myometrium
Departments of Obstetrics and Gynecology [J. C. M. T., K. B. P., A. J., H. H., K. K., G. W. P., W. F. O., W. N. S.] and Biochemistry and Molecular Biology [J. C. M. T.], University of South Florida, Tampa, Florida 33606, and Institute for Clinical Pharmacology and Toxicology, Free University of Berlin, D-14195 Berlin, Germany [G. T., H. N.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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(PPAR), retinoid X receptor 
proteins, and all-trans retinoic acid, but only during the follicular phase of the menstrual cycle. 9-cis Retinoic acid was undetectable in either leiomyomata or myometrium. PPAR mRNA levels were lower in leiomyomata than myometrium, but only during the luteal phase of the cycle. A PPAR agonist, troglitazone, was given to guinea pigs along with estradiol and all-trans retinoic acid and produced the largest leiomyomata seen to date in this model. By contrast, no tumors formed when troglitazone was given alone or with estradiol or when troglitazone was given with estradiol and 9-cis retinoic acid. New therapies for human leiomyomata may emerge by combining antagonists for PPAR and retinoid X receptor with selective estrogen receptor modulators. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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The cause of leiomyomata is unknown, but estrogens produced by leiomyoma aromatase are suspected to promote their growth (4)
. Rodent models for uterine leiomyomata include the Eker rat (5)
, carrying a mutation in the tuberous sclerosis-2 gene, and two transgenic mice (6
, 7)
. In our guinea pig model, exposure solely to E27
silastic implants was associated with leiomyomata forming mainly on the abdominal wall, whereas exposure to E2 and retinoic acid implants "switched" leiomyoma formation to the uterus (8)
. This observation prompted us to test human leiomyomata for the expression of RARs and RXRs and for other members of the ligand-activated nuclear receptor superfamily (9)
. Encouraging immunoblot data focused our attention on PPAR and RXR and their potential relevance to the regulation of leiomyoma growth.
PPAR, one of three mammalian PPAR isoforms (, 
/
, and ), is found in adipose tissues, where it mediates adipocyte differentiation (10)
, and other insulin-responsive tissues such as skeletal muscle and liver (11, 12, 13, 14, 15)
. RXR is regarded as the master nuclear receptor because it forms heterodimers with RAR, PPAR, vitamin D3, or thyroid hormone receptors (9)
. In the presence of a PPAR ligand, PPAR-RXR heterodimers are formed and bind to peroxisome proliferation-responsive elements; the heterodimers are considered the functionally active receptor forms in vivo.
Retinoic acids are the biologically active form of vitamin A; atRA and 9cRA can be isomerized to each other both in vivo and in vitro. RARs (RAR, RAR, and RAR) bind atRA and 9cRA. The RXR, RXR, and RXR bind 9cRA. RAR and RXR are encoded by different genes, and each subtype (, , and ) differs mainly in their NH2 terminus because of alternate mRNA splicing and use of different promoters.
Naturally occurring ligands for PPAR are unsaturated fatty acids and prostaglandins (12
, 14
, 16
, 17)
. PPAR is found in the small intestines and colon, and as the receptor for fatty acids, PPAR may have a primary role in colon cancer (18)
. Natural and synthetic PPAR ligands, such as Tro, a thiazolidinedione, are sufficient to stimulate adipocyte differentiation in fibroblast-like preadipocytes (11
, 14)
. The ability of Tro to bind and activate PPAR correlates with its ability to improve insulin sensitivity in type II diabetic patients and in animal models of diabetes and obesity (11, 12, 13, 14)
.
Our in vivo guinea pig experiment with Tro (19)
demonstrated that sustained exposure to E2, Tro, and atRA were optimal for uterine leiomyoma growth in this model. On the basis of comparable findings in human leiomyomata, we hypothesize that new therapeutic modalities for human leiomyomata could be based on antagonists for PPAR and RXR, given singly or in combination with SERMs.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Frozen human and animal tissues were finely cut and placed (at 150 mg wet tissue/ml) in a Tris-HCl (pH 8) buffer containing aprotinin, NP40, NaCl, NaF, phenylmethylsulfonyl fluoride, orthovanadate, and leupeptin (20) and were extracted overnight at 4°C with gentle tumbling. Recently, in a few homogenizations, we included 20 µM of the cathepsin-L/calpain inhibitor Z-Leu-Leu-Tyr-fluoromethyl ketone from Enzyme Systems Products (Livermore, CA). After 15 s of Tekmar homogenization and 2 h of tumbling, the homogenates were centrifuged at 14,000 x g for 30 min. In the supernatant, protein was measured with the BCA kit from Pierce (Rockford, IL) using BSA as a standard.
Guinea Pig Studies.
Dunkin-Hartley female guinea pigs (Cavia porcellus) were used in this study and received one or two silastic implants (21)
of E2 (each contained 50 mg of powder), an implant of atRA from Sigma Chemical Co. (St. Louis, MO) or 9cRA (a gift from Hoffmann La-Roche, Nutley, NJ), each containing 40 mg of powder, and a small identification chip from AVID (Norco, CA) in the s.c. space of the intrascapular area after a bilateral oophorectomy via laparotomy (or sham operation) in the costovertebral angle. Anesthetics were administered as described before (22)
. Tro (Rezulin tablets) from Parke-Davis (Ann Arbor, MI) was suspended in an aqueous solution of 1% carboxymethylcellulose, 0.81% NaCl, and 0.1% Tween 80 and given daily p.o. at a dose of 10 mg/kg body weight in 1 ml, followed by 1 ml of fruit punch. All animals were weighed weekly.
Western Blotting.
NuPage Bis-Tris 4–12% gels from Novex (San Diego, CA) and recombinant S-tagged molecular weight markers from Novagen (Madison, WI) were used; 50–100 µg protein were loaded per lane. Polyclonal antibodies to RAR-2-, RXR (SC-552, epitope at NH2 terminal), RXR- from Santa Cruz Biotechnology (Santa Cruz, CA) and Affinity Bioreagents (Golden, CO), monoclonal RXR antibody 4RX3A2 (a gift from Dr. P. Chambon, IGBMC, Illkirch, France), and an antibody (15)
to recombinant PPAR2 (a gift from Dr. B. Spiegelman, Dana-Farber Cancer Institute, Boston, MA) were used. Equal lane loading was confirmed either by an -desmin antibody from Sigma Chemical Co. (St. Louis, MO) or by protein staining of the nitrocellulose membrane with BLOT-FastStain from Geno Technology (St. Louis, MO), followed by destaining, blocking, and exposure to the primary antibody. Secondary antibodies were from Amersham (Arlington Heights, IL) and Novagen, and chemiluminescence kits were from Amersham.
Northern Blots.
Total RNA was isolated with the TRI reagent from MRC (Cincinnati, OH), and poly(A)+ RNA from total RNA using the Oligotex kit from Qiagen (Valencia, CA). Prehybridization and washings were carried out at room temperature with MRC solution WP-117, and hybridizations were performed at 65°C with MRC solution HS-114. cDNA probes (14)
for PPAR, RXR (gifts from Dr. B. Spiegelman), and -desmin (a gift from Dr. Y. Capetanaki, Baylor College of Medicine, Houston, TX) were labeled with the random-primed DNA labeling kit from Boehringer-Mannheim (Indianapolis, IN) and [-32P]dCTP (6000 mCi/mol) from NEN (Boston, MA) and were purified with the DNA Clean-up kit from Promega (Madison, WI).
Analysis of Retinoids by HPLC.
All procedures were performed under dim light to prevent photoisomerization of retinoids. Serum samples were extracted with 2-propanol, as described previously (23)
. Uterine tissues (200–400 mg) were cut frozen in 2-mm pieces and extracted for 5 min with three volumes of ice-cold 2-propanol, containing 13 µg of butylated hydroxytoluene/ml as antioxidant, followed by 10-min sonication at 4°C and shaking for 5 min at room temperature. Precipitated cell debris and proteins were removed at 6500 xg, and the supernatant solutions from either serum or tissues were extracted on a C2 solid-phase cartridge to recover the retinoids and remove interfering substances (24)
. The cartridges were loaded into the HPLC system, and separation of retinoids was achieved on a C18 column with gradient elution within 28 min; this method can resolve 17 retinoids (24
, 25)
. Criteria for identification of HPLC peaks were the coincidence of retention time and ratio of peak areas at two wavelengths of detection with those of authentic retinoids. For identification of some retinoids, HPLC fractions were collected and rechromatographed, and UV spectra were recorded at 300–370 nm in the flow cell of the UV detector (26)
. An isocratic method (25
, 27)
was used for rechromatography of the putative atRA peaks from the uterine samples; this method can resolve 13cRA, 9,13-di-cRA, 9cRA, and atRA.
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RESULTS AND DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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. In women, however, leiomyomata are restricted to the uterus and rarely form in the abdominal cavity (leiomyomatosis peritonealis disseminata), lungs, digestive tract, or arteries. To establish the mechanism of leiomyoma growth and ultimately reverse the disease, we exposed (8)
ovariectomized guinea pigs for 260–300 days to one or two E2 implants plus one atRA (n = 12) or one implant each of E2 and 9cRA (n = 5). The E2 implants, with or without 9cRA or atRA implants, maintained serum E2 levels in ovariectomized animals at 30–90 pg/ml (gestational levels in the guinea pig) for up to 400 days (21)
. Mean serum retinol (±SE, n = 8) was 270.5 ± 20.0 ng/ml, retinyl palmitate/oleate was 22.7 ± 4.2, and retinyl stearate was 35.2 ± 6.1 at 260–300 days of treatment; serum 13cRA was 4.7 ± 0.6 (n = 6), but atRA and 9cRA were detectableM only in six animals at 
0.6 ng/ml.
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. The tumors were leiomyomata, as verified by electron microscopy and desmin immunostaining (data not shown). In the absence of E2, atRA or 9cRA produced no leiomyomata. Animals on E2 and either atRA or 9cRA survived beyond 400 days, whereas treatment solely with E2 (21)
for longer than 7 months produced extensive abdominal tumors, causing intestinal obstructions that forced the termination of the experiments.
Receptor Levels in Leiomyomata.
Nuclear receptor RAR (, , and ), RXR (, , and ), and PPAR protein levels were determined by immunoblotting of tissue extracts of human leiomyoma and myometrium and guinea pig leiomyoma and uterine horn cross-sections. PPAR and RXR expression were higher in human leiomyomata than myometrium, but only in the follicular phase; higher levels were noted in guinea pig leiomyomata relative to uterine horn cross-sections (Figs. 2
and 3
).
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and RXR levels or between the PPAR leiomyoma:myometrium ratios and body mass index. RAR, RAR, or RAR levels were not consistently different between leiomyomata and myometrium (data not shown). The RXR immunoblots with an antibody to a RXR NH2-terminal segment (Fig. 3)
suggested that the native RXR form (Mr 50,000) was partially degraded; the degradation was more pronounced in the human than guinea pig tissue extracts. The Mr 50,000 and Mr 35,000 bands were included in RXR quantitation (Fig. 3)
. Monoclonal antibody 4RX3A2 to human RXR gave nearly identical immunoblots as those in Fig. 3
(data not shown), but it did not react with the guinea pig samples. Recently, it was reported that cathepsin-L partially degrades RXR (28
, 29)
. We tested in eight samples whether 20 µM Z-LLY-FMK, a new cathepsin-L/calpain inhibitor, added during human tissue homogenization would prevent RXR degradation. Indeed, the main RXR band was now at Mr 50,000 in both myometrial and leiomyoma immunoblots (data not shown), suggesting that the partial proteolysis of RXR seen in earlier blots (Fig. 3)
occurred during tissue homogenization by a protease(s) inhibited directly or indirectly by Z-LLY-FMK. Interestingly, Z-LLY-FMK reduced the -desmin bands to two, at Mr 50,000.
In women, the 3- to 5-fold higher expression of PPAR and RXR in leiomyomata depended on the phase of the menstrual cycle (Fig. 4)
. Perhaps, in the follicular phase E2, unopposed by progesterone, is the primary stimulus for increased PPAR and RXR expression, leading to leiomyoma growth. It is possible that progesterone could decrease PPAR or RXR expression directly, not through decreased E2 receptor concentration.
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and RXR were performed. Fig. 5
shows that PPAR and RXR mRNAs were equally expressed in human myometrium and leiomyomata throughout the menstrual cycle, except for PPAR mRNA levels that were lower in leiomyomata than myometrium (P < 0.002) only in the luteal phase. Another Northern blot of RXR using total RNA samples from three uteri in the luteal phase also showed equal mRNA levels between leiomyomata and myometrium (data not shown). Reverse phase-PCR showed that mRNA for total PPAR (segment 146–620; Ref. 30
) and RXR (segment 1318–1430; Ref. 31
) were expressed in both myometrium and leiomyoma throughout the cycle (data not shown).
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showed 4.5-fold higher atRA levels in leiomyomata than myometrium in the follicular phase only. By contrast, the presence of atRA in the luteal phase was not confirmed because of interferences that coeluted with atRA; 9cRA was not detectable. Retinol (vitamin A) levels were 25% lower in follicular phase leiomyomata than myometrium (Fig. 6)
and 35% lower in luteal phase leiomyomata than myometrium (data not shown). Retinyl ester levels were undetectable in most of these tissues, or when detected, did not exceed 15 ng/g, a much lower content than retinol. Lower retinyl ester levels than retinol are also found in guinea pig uterine tissues (data not shown) and in rodent embryos of 11–12 days gestational age (27)
.
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expression was higher in human leiomyomata, we tested in guinea pigs whether a PPAR agonist, Tro, could cause leiomyomata. Tro was given daily for 75 days p.o. (10 mg/kg) to seven ovariectomized guinea pigs primed for 150 days with two E2 (n = 2) and either one atRA (n = 2) or 9cRA (n = 3) implant; two other animals received Tro only for 75 days. Only combined exposure to E2, atRA, and Tro produced uterine leiomyomata, 4-fold larger than seen previously in the guinea pig (Fig. 7e
; 4 cm at largest dimension). Tro alone had no effect on the atrophic uterus of the ovariectomized animals (Fig. 7b)
and even prevented abdominal leiomyoma formation in animals treated with E2 (Fig. 7c)
. The apparent increase of abdominal fat attributable to Tro alone (Fig. 7a)
was not accompanied by weight gain during the 75-day treatment with Tro. Unexpectedly, the combination of 9cRA with E2 and Tro produced neither uterine or abdominal leiomyomata (Fig. 7f)
, although 9cRA and E2 produced uterine leiomyomata (Fig. 1, c and d)
.
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and RXR showed (Fig. 8)
that Tro given either alone or with E2 induced measurable PPAR and RXR levels both in the atrophic (Lanes 1a and 1a') and the E2-stimulated uterine horn (Lanes 5a and 5a'); the distribution of these receptors between myometrium and endometrium has not yet been determined. It appears that relatively high expression of PPAR and RXR in the uterine horns (Lanes 1 and 5) does not support leiomyoma formation. Rather, a combination of additional stimuli, E2 and atRA, is needed for tumor formation.
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and RXR proteins in follicular phase leiomyomata reflects an increase of the transcriptionally active PPAR:RXR heterodimer, and that the latter is a key to leiomyoma growth. This heterodimer was suggested as a single-function complex and a molecular target for treatment of insulin resistance because of beneficial effects seen in diabetic patients treated with the PPAR agonist Tro and in animal models treated with RXR agonists and, surprisingly, antagonists of RXR (32)
. In leiomyomata, we do not know the inducers of the putative PPAR:RXR complex or whether estrogens alone stimulate PPAR and RXR expression and higher atRA levels. Estrogens induce the formation of a prostaglandin D2 metabolite that activates PPAR in the duck uropygial gland (33)
. In the guinea pig model (Fig. 1)
, E2 stimulation is necessary but not sufficient for uterine leiomyoma growth. Estrogens are considered beneficial to insulin resistance, although they correlate with obesity in women. A modest increase in relative risk (confidence interval, 1.03–1.59) for uterine leiomyomata with elevated body mass index was reported recently in a large study of adult women (34)
.
Additional studies will determine whether "downstream" factors, such as nuclear receptor coactivators, corepressors, and histone acetyltransferases (35)
are differentially expressed and important for leiomyoma growth, in addition to "upstream" inducers of retinol activation, 15-lipoxygenase and prostaglandin D and J biosynthesis that may act in leiomyomata. Undoubtedly, vitamin D3 receptors participate in the development of the leiomyoma phenotype, such as calcification foci, common to human and guinea pig leiomyomata (Fig. 7e
; data not shown).
Fig. 9
summarizes our results on the pathways to leiomyoma formation. Three "inducers" are proposed as prerequisites of uterine leiomyoma development and growth, i.e., E2 stimulation in the absence of progesterone, higher atRA levels, and higher PPAR-RXR levels. Unlike "hits" leading to malignant transformations (36)
, this mechanism implies that leiomyoma growth is potentially reversible by lowering "inducer" levels, as shown in women who become hypoestrogenic by gonadotropin-releasing hormone agonist therapy (3)
.
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A direct link at the molecular level between estrogens and the retinoid pathway (RAR, RXR, PPAR) has not been established in leiomyomata. Two reports (38
, 39)
, awaiting confirmation by other laboratories, suggested that in vitro heterodimers form between either RAR or RXR and the ER and ; no evidence was offered about PPAR-ER dimers. One explanation why guinea pigs treated with E2-9cRA-Tro (Fig. 7f)
did not develop leiomyomata could be that increased 9cRA favors RXR homodimerization, in effect, removing RXR from transcriptionally active RXR-PPAR or other heterodimers. Perhaps 9cRA alone would be beneficial to patients with leiomyomata. In the model, the ability of 9cRA and E2 to produce small uterine leiomyomata in the absence of Tro (Figs. 1
and 9
) points to a pathway that does not require further induction of PPAR. The fact that Tro in the presence of E2 prevented even abdominal leiomyoma formation (Figs. 7c
and 9
) may imply that leiomyoma formation relies on a narrow heterodimer stoichiometry, which can be disturbed by receptor agonists and antagonists.
In the follicular phase of the menstrual cycle, under the influence of elevated E2 and atRA, increased levels of the putative ER-RAR and ER-RXR heterodimers could form, along with RXR-PPAR heterodimers stimulated by endogenous PPAR ligands, also under the control of estrogens (33)
. Anzano et al. (40)
and Keller et al. (41)
were first to suggest an interaction between estrogen action and RXRs/or 9cRA and/or PPARs, respectively. Nu
ez et al. (42)
also reported that RXR and PPAR are capable of activating estrogen-responsive genes by direct binding to estrogen response elements.
In the luteal phase, E2 levels are lower than those at the preovulatory stage, and rising progesterone could down-regulate essential heterodimers, causing arrest of leiomyoma cell growth (increase in cell size, hypertrophy) and initiation of mitosis (hyperplasia); more mitotic indices are found in human leiomyomata during the luteal than follicular phase (43) .
Potential New Therapies for Leiomyomata.
If a mechanism of three principal "inducers" controls leiomyoma growth (Fig. 9)
, it is reasonable that new therapies should target these "inducers." A synergistic interaction between the antagonists would lower each antagonist’s effective dose for tumor regression and would minimize side effects. For example, the SERM raloxifene (44)
or LY383351 (45)
given p.o. will undoubtedly cause leiomyoma regression. However, suboptimal SERM doses for leiomyoma monotherapy combined with PPAR antagonists (under development) or RXR antagonists and agonists (now in clinical trials for type II diabetes and breast cancer) may offer an advantage as new combination therapies for leiomyomata. Moreover, some of these heterodimers in leiomyomata may have redundant functions, as seen in other systems (46)
, and it may be necessary to target all three leiomyoma "inducers" to account for individual differences in endogenous receptor inducers and isoforms; even among separate leiomyomata from one uterus, the levels of PPAR and RXR proteins are not identical. Vaginal application or in situ (laparoscopic) delivery to the tumors may be preferable than oral administration of the antagonists. At present, there are no tissue-selective inhibitors of enzymes, e.g., retinol oxidases, to test the effect of lowering leiomyoma atRA levels.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Department of Obstetrics and Gynecology, University of South Florida, 4 Columbia Drive, Room 524, Tampa, FL 33606. Phone: (813) 254-7774; Fax: (813) 254-0940; E-mail: jtsibris{at}com1.med.usf.edu 
2 Present address: Department of Obstetrics and Gynecology, Texas Tech University, 3601 4th Street, Lubbock, TX 79430.
3 Present address: Tzimas-Dimolios, Inc., Edessis 3, Thessaloniki, GR-54625, Greece.
4 Present address: Department of Food Toxicology, School of Veterinary Medicine Hannover, D-30173 Hannover, Germany.
5 Present address: Department of Radiology, University of Minnesota Medical School, Box 292, 420 Delaware Street, S.E., Minneapolis, MN 55455.
6 Present address: Zhordania Institute of Human Reproduction, 380009 Tbilisi, Georgia.
7 The abbreviations used are: E2, 17-estradiol; PPAR, peroxisome proliferator-activated receptor ; RXR, retinoid X receptor; atRA, all-trans retinoic acid; 9cRA, 9-cis RA; 13cRA, 13-cis RA; Tro, troglitazone; SERM, selective estrogen receptor modulator; HPLC, high-performance liquid chromatography; ER, E2 receptor.
Received 5/21/99. Accepted 9/22/99.
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