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From the * Department of Anatomy, Cell Biology,
Physiology, and Biophysics, Institute of Biology, State University of Campinas
(UNICAMP), Campinas SP, Brazil; and the
Department of Animal Reproduction, College of
Veterinary Medicine and Animal Sciences, University of São Paulo,
São Paulo SP, Brazil.
| Correspondence to: Hernandes F Carvalho, Department of Anatomy, Cell Biology, Physiology, and Biophysics–UNICAMP, CP6109, 13083-863 Campinas SP, Brazil (e-mail: hern{at}unicamp.br). |
| Received for publication February 22, 2010; accepted for publication May 24, 2010. |
Prostate growth and physiology are regulated by steroid hormones and
modulated by multiple endocrine factors. We investigated the action of insulin
on the tissue organization and kinetics of epithelial cells in the rat ventral
prostate (VP) in response to castration up to 120 hours after surgery by using
an acute protocol of alloxan-induced diabetes. Diabetes caused a reduction in
volume density (Vv%) and volume of the epithelium. The effects of
castration on the epithelium were accelerated in the diabetic animals, as
determined by changes in Vv% and volume. The smooth muscle cells
became atrophic and apparently relaxed in response to castration, in contrast
to the spinous aspect observed in nondiabetic castrated rats. Counting of
apoptotic nuclei in the epithelium showed the classical apoptosis peak at 72
hours in nondiabetic rats and an advance of the apoptosis peak to 48 hours
after castration in diabetic rats. Insulin restored the time of the peak to 72
hours. These results were confirmed after immunostaining for cleaved caspase-3
and suggest a survival and antiapoptotic effect on VP epithelial cells in both
the presence and absence of androgen stimulation. This idea is supported by
the observation that insulin also reduced the overall rate of apoptosis at all
experimental points analyzed before and after castration.
Key words: Apoptosis, tissue remodeling
Surgical castration of rodents causes almost complete elimination of circulating testosterone. This decrease takes place as soon as 3 hours after surgical removal of the testes (Kashiwagi et al, 2005). This results in regression of the prostate, which involves endothelial cell death and other vascular alterations (Shabsigh et al, 1998; Johansson et al, 2005), the death of epithelial cells (Kerr and Searle, 1973; Kyprianou and Isaacs, 1988; Isaacs et al, 1994), and additional, marked changes in stromal smooth muscle cells and the extracellular matrix (Carvalho and Line, 1996; Carvalho et al, 1997a,b; Vilamaior et al, 2000, 2005; Antonioli et al, 2004, 2007; Augusto et al, 2008).
Chimerical prostate tissue recombinants revealed that androgen deprivation can induce epithelial regression even in AR-deficient epithelial cells, suggesting that epithelial cell apoptosis is mediated by stromal factors (Kurita et al, 2001), including changes in the vascular bed (Buttyan et al, 2000). These observations have led to a search for the factors mediating the stromal and epithelial paracrine interactions between epithelium and stroma.
We have been intrigued by the timing of the major peak of epithelial cell apoptosis 72 hours after castration, although the drop in serum testosterone occurs much earlier (Kerr and Searle, 1973; Kyprianou and Isaacs, 1988; Isaacs et al, 1994; Bruni-Cardoso et al, 2010). In fact, administration of a high dose of 17β-estradiol (E2) to castrated rats altered the kinetics of epithelial cell apoptosis in the rat ventral prostate (VP) and revealed the existence of independent androgen deprivation and estrogen-induced apoptotic pathways (García-Flórez et al, 2005).
The hypothesis of this study was that somatotropic hormones could influence androgen dependency and buffer variations in androgen levels, connecting the local events taking place in the prostate gland with systemic endocrine regulation. Considering that insulin plays such an integrative role in the organism and that insulin levels show good correlation with prostate size by modulating epithelial cell proliferation (Yono et al, 2005; Vikran et al, 2009), we decided to study the effect of insulin on tissue changes and on the kinetics of epithelial cell apoptosis in the rat ventral prostate after castration. Using a model of alloxan-induced diabetes to follow tissue parameters and apoptosis rate on a daily basis (up to 120 hours after castration), we obtained a series of results demonstrating that insulin represents an important survival factor for the prostate epithelium in an androgen-deprived environment, affecting the rate of epithelial cell apoptosis in the rat VP in response to castration.
Materials and Methods
Animals, Treatments, and Tissue Processing
Seventy-two Wistar male rats aged 75 to 105 days were used. The animals
were kept under normal light conditions and received filtered tap water and
Purina rodent chow ad libitum. Forty-eight animals received 1–3
intraperitoneal injections of 75 mg/kg alloxan (5,6-dioxyuracil monohydrate;
Sigma Chemical Co, St Louis, Missouri) in 0.1 M citrate buffer, pH 4.4, at
7-day intervals. Before the injections, the animals were fasted for 24 hours
and tested for glucosuria and glycemia. Once the animals were determined to
have glucosuria (>28 mmol/L) and high glycemia (>350 mg/dL), the animals
received an extra injection of alloxan (stabilizing dose) 7 days later.
Insulin concentration was below the radioimmunoassay detection levels.
Twenty-four animals received exogenous NPH insulin (20 U/kg body weight;
Biobrás, Montes Claros, MG, Brazil) twice a day (at 0600 and 1800
hours) beginning 24 hours after the stabilizing alloxan injection. This
treatment reversed the glucosuria and hyperglycemia. Twenty animals from each
group (nondiabetic, diabetic, and diabetic plus insulin) were castrated
through scrotal incision under ketamine (80 mg/g body weight) and xylazin (10
mg/g body weight) anesthesia 48 hours after the stabilizing alloxan injection.
They were then killed at 24-hour intervals up to 120 hours, resulting in 4
animals per time point per group.
After they were killed by an overdose of anesthetics, the animals were weighed, blood was sampled for the determination of testosterone plasma levels, and the ventral prostates were removed, weighed, and fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) for 24 hours. Fixed prostates were then routinely processed for paraffin or historesin embedding.
Procedures were approved by the University Committee for Ethics in Animal Experimentation (Protocol 1489-1).
Determination of Testosterone Plasma Levels
Plasma was separated by centrifugation and stored at +20°C until used.
Testosterone and E2 concentrations in the plasma were determined by
radioimmunoassay with the use of the Coat-A-Count kit (Diagnostic Products,
Los Angeles, California). The sensitivity of the tests was 1.08 ng/dL, and the
coefficient of variation was 2.33%.
Histology and Stereology
Historesin sections (2 µm) were stained with hematoxylin and eosin for
general histology and stereology according to Huttunen et al
(1981), as previously
described (Antonioli et al,
2004;
García-Flórez et al,
2005). Volume density (Vv%) of the epithelium, lumen,
stroma (stromal compartment less the smooth muscle cells), and smooth muscle
cells was determined from 6 microscope fields per animal (n = 24). As part of
an exploratory analysis, the volume of each compartment was determined from
the mean weight of the ventral prostate, assuming a tissue specific gravity of
1 g/mL (DeKlerk and Coffey,
1978).
Determination of the Apoptotic Index
Apoptotic cells were counted by identification of apoptotic nuclei after
the Feulgen reaction and after the terminal deoxynucleotidyl
transferase–mediated dUTP nick end labeling (TUNEL) reaction. Historesin
sections were hydrolyzed for 1 hour and 32 minutes in 4 N HCl and then
incubated with Schiff's reagent for 45 minutes. After extensive washing, the
sections were dehydrated and mounted in Entellan. Six microscope fields per
animal (n = 24) were taken at random, and the apoptosis index was determined
by dividing the number of apoptotic nuclei by the number of total epithelial
cell nuclei in each microscope field, using a x100 objective. The TUNEL
reaction was performed using an in situ cell death detection kit (Roche
Diagnostics, Indianapolis, Indiana) to detect DNA fragmentation, following the
manufacturer's instructions. Counting was done as above. Cleaved caspase-3 was
located by immunohistochemistry with the use of an anti–cleaved
caspase-3 antibody (Cell Signaling Technology, Danvers, Massachusetts) and a
routine protocol for immunohistochemistry employed in the laboratory
(Augusto et al, 2008). Cleaved
caspase-3–positive cells were counted as above.
Statistical Analysis
Statistical analyses were performed by analysis of variance followed by the
multicomparison post hoc Tukey's test, at P < .05, with a free
trial version of Minitab software.
Results
Morphometrics—Variation of Body and Prostate Weights
Treatments did not affect Wistar rat body weight within the timeline of the
experiment. Castration of the diabetic animals showed a transient
nonsignificant decrease in body weight
(Figure 1A), and this variation
was not seen with simultaneous administration of insulin.
|
Effects on Plasma Testosterone
The concentration of plasma testosterone was 334.6 ± 204.2 ng/dL.
Diabetes induction caused a reduction of about 50% in this number (160.0
± 52.3 ng/dL), even though in the present experimental conditions and
sample size it did not achieve statistical significance. The testosterone
concentration partly recovered (217.7 ± 110.0 ng/dL) after insulin
administration. Castration caused a more than 99% reduction in testosterone
levels in animals of all 3 experimental groups as early as 24 hours after
castration.
Variations in Tissue Organization
The VP is a tubulo-acinar structure surrounded by a cylindrical,
single-layered epithelium. The lumen is usually large and filled with
secretory material. The stromal compartment has sparse cellular and fibrous
material. A single layer of smooth muscle cells surrounds the epithelium
(Figure 2A). During the
timeline of the experiment, diabetes caused few changes in the VP. There was a
small reduction in epithelial cell height and a decrease in the secretory
content in the acini (Figure
2C). Insulin administration to the diabetic rats affected the
growth of the epithelium, which showed an increase in the epithelial infolds,
similar to that found in the distalmost ductal regions
(Lee et al, 1990). No evident
effect of diabetes or insulin administration on diabetic rats was observed in
the stroma of noncastrated rats within the timeline of the experiment.
Castration caused marked modification of the VP histology. The epithelial
cells became short, the lumen was reduced, and the stroma became denser, with
many cell types, including mast cells and more evident collagen fibers, 120
hours after castration (Figure
2B). The modifications of the smooth muscle cells consisted of the
acquisition of a spinous aspect (irregular outline) and the adoption of a
multilayer organization around the regressing epithelium, similar to previous
reports (Antonioli et al, 2004,
2007).
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Stereology demonstrated that the epithelium is the predominant compartment of the VP, corresponding to a volume density (Vv%) of 47% and a mean volume of 153 µL in noncastrated nondiabetic animals (Figure 3A and E). Induction of diabetes caused a reduction in the Vv% and volume of the epithelium. Insulin administration did not reverse this reduction within the timeline of the experiments (Figure 3A and E). Counterbalancing this reduction in the epithelium was an increase in the Vv% of the lumen, which was even larger after administration of insulin (Figure 3B). These variations were insufficient to cause a significant change in the volume of the lumen (Figure 3F). Stromal Vv% and volume were not affected within the timeline of the experiment (Figure 3C and G), considering the short period of exposure to the diabetic condition and insulin administration. Similar to the epithelium, the Vv% of the epithelium and the volume occupied by smooth muscle cells was smaller in diabetic animals, and even smaller after treatment with insulin (Figure 3D and H).
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Castration had little effect on the luminal and stromal Vv% and volume up to 120 hours after surgery in the 3 experimental groups (Figure 3B and C, 3F and G). Androgen deprivation caused no reduction in the Vv% and volume of the smooth muscle cells in nondiabetic animals but promoted significant reduction in the Vv% and volume observed in diabetic animals. Insulin reverted this effect, and no significant reduction was observed in insulin-treated diabetics (Figure 3D and H), confirming the histological observations described above.
Kinetics of Apoptosis After Castration
Feulgen-stained prostate sections allowed for the identification of
apoptotic nuclei, which were characterized by pyknosis or fragmentation
(Figure 4A). The percentage of
apoptotic nuclei identified after the Feulgen reaction in the VP in intact
rats was 0.7%. Diabetes induction by alloxan did not affect this percentage.
However, insulin administration to diabetic rats caused a 92% reduction in the
number of apoptotic nuclei (Figure
4A). Orchiectomy caused a 550% increase in the apoptotic index 72
hours after surgery. Ninety-six hours after castration, this index dropped
32%, returning to basal levels by about 120 hours
(Figure 4A). In diabetic rats,
there was an advance of the 72-hour peak to 48 hours
(Figure 4A). Insulin
administration caused significant reduction in the percentage of apoptotic
nuclei in noncastrated rats and at different time points after castration, in
addition to restoring the peak to 72 hours
(Figure 4A).
|
Identification and counting of cleaved caspase-3 showed a similar kinetics of apoptosis under the 3 experimental conditions, especially by demonstrating an advance of the peak found at 72 to 48 hours in diabetic rats and an overall reduction in the number of apoptotic cells after insulin administration to diabetic rats (Figure 4C). The numbers obtained after counting cells immunostained for cleaved caspase-3 were 2-fold higher than those obtained for apoptotic nuclei.
Discussion
In the present study, we demonstrated that insulin regulates the regressive changes of the VP in response to castration by affecting the histological organization of the epithelial and smooth muscle cells and by modulating the kinetics of epithelial cell apoptosis. Using a combination of an acute model of alloxan-induced diabetes and insulin administration, we found that diabetes caused a reduction in the volume of the smooth muscle cells with clear signs of atrophy and also accelerated the epithelial regression after castration. This latter observation was associated with an advance of the peak of epithelial apoptosis from 72 to 48 hours in the absence of insulin (ie, diabetic animals), and a return of this peak at 72 hours on insulin administration. Additionally, we have also shown that insulin modulates the rate of epithelial cell apoptosis in noncastrated animals, as well as after castration, which suggests that insulin plays an important role as a survival factor for the epithelial cells in both the presence and absence of androgen stimulation.
The acute alloxan-induced diabetes protocol employed here was chosen to prevent the cumulative changes in the organ described in experimental diabetes (Carvalho et al, 2003; Yono et al, 2005; Ribeiro et al, 2008). This protocol caused no alteration in the VP weight in noncastrated rats, in contrast to what was found after chronic protocols employed by others (Yono et al, 2005; Ribeiro et al, 2008), who attributed the reduced weight to low circulating testosterone levels attained after long-term diabetes. However, it appeared that the acute protocol was not enough to achieve consistently reduced testosterone and promoted reduced effects on the epithelial cell structure.
Castration caused a significant reduction in the VP weight in nondiabetic and diabetic animals and in diabetic animals that received insulin. Whereas the nondiabetic rats showed significant VP weight loss only by 96 hours after castration, in the diabetic rats, this maximum weight loss was observed at 72 hours, and in those that received insulin, this reduction was achieved even earlier, at 48 hours after castration, showing that insulin affected weight loss after castration. The maximum weight reduction for the 3 experimental groups 120 hours after castration corresponded to about 66% of the VP relative weight. To understand this effect, we examined the changes in histology and organization of the tissue compartments, as well as the kinetics of epithelial cell apoptosis.
As demonstrated by stereology, the epithelial and smooth muscle cell compartments were the most affected after the acute model of alloxan-induced diabetes, whereas little effect was seen in the luminal and stromal compartments. Maximum reduction of epithelial volume was anticipated in diabetic rats compared with nondiabetic rats (24 hours compared with 120 hours, respectively). Administration of insulin to diabetic rats restored the pattern observed in nondiabetic rats.
Curiously, the maximum reduction observed in the epithelium in nondiabetic animals did not differ from that observed in diabetic animals. Taken together, these results reinforce the idea that progressive regression depends on stromal remodeling, which was previously suggested by García-Flórez et al (2005) and confirmed recently in a detailed study of MMP-2, -7, and -9 expression in the VP after castration (Bruni-Cardoso et al, 2010).
Diabetic animals showed smaller smooth muscle cell volumes, which was consistent with their atrophic histological appearance. Within the timeline of the experiment, very little effect was observed on the volume of the smooth muscle cells in nondiabetic rats, suggesting that at least 1 week of androgen deprivation is necessary to achieve significant alterations in the smooth muscle volumes in the VP (Antonioli et al, 2005). However, these cells became even more atrophic in the diabetic rats, and this effect was not reversed by insulin, causing both groups to show significantly smaller smooth muscle cell volumes 120 hours after castration, compared with the nondiabetic rats. Accordingly, insulin is an important factor for the maintenance of smooth muscle cells in culture (Gerdes et al, 1996).
The reduction of epithelial cells in response to castration is partially attributed to their deletion by apoptosis. Kinetics of epithelial cell death shows a classical peak at 72 hours after castration (Kerr and Searle, 1973; Kyprianou and Isaacs, 1988; Isaacs et al, 1994). Here, we show that the peak of apoptosis is advanced to 48 hours in diabetic animals and restored to 72 hours on insulin administration. The results are based on cell counts made after Feulgen staining, TUNEL labeling, and cleaved caspase-3 immunostaining. The first 2 approaches have been used before and were shown to be comparable (Bruni-Cardoso et al, 2010). Notably, the number of cells stained for cleaved caspase-3 was 2-fold higher than the number of apoptotic nuclei, probably because the former stains the cytoplasm and has a better chance of being sampled in a tissue section with the same thickness. We also showed that insulin administration reduced the overall rate of apoptosis in both noncastrated and castrated animals. Insulin levels are positively correlated with VP size (Vikran et al, 2009), and blocking insulin production during sexual maturation compromises prostate growth (Soudamani et al, 2005). This occurs because insulin regulates the production of testosterone by affecting the hypothalamic-hypophyseal-testes axis (Kirchick et al, 1979) and producing local effects through insulin receptors (Stattin et al, 2001). In addition to these growth-promoting effects, the present results suggest that insulin also functions as a survival and antiapoptotic factor for the VP epithelium, in either the presence or absence of androgen stimulation (ie, before and after castration).
Insulin-like growth factor 1 (IGF-1) was identified as a major regulator of epithelial cell survival in the rat VP, which is lost by androgen deprivation (Ohlson et al, 2006). Androgen deprivation led not only to the reduction in local production of IGF-1, but also increased IGF binding proteins (IGFBPs; especially IGFBP-3, which is involved in mediating epithelial cell apoptosis) (Firth and Baxter, 2002) and reduced the ability of the surviving cells to respond to exogenous IGF-1 by reducing the amount of insulin receptor substrate 1 (IRS-1) and increasing its level of inhibitory phosphorylation at serine 307 (Ohlson et al, 2006). On the other hand, type I IGF receptor conditional abrogation led to uncontrolled epithelial cell proliferation and prostate hyperplasia (Sutherland et al, 2008). These changes in IRS-1 are, at least in part, responsible for the peripheral resistance to insulin in castrated animals and its reversal in response to testosterone (Holmang and Bjorntorp, 1992) and seem to be responsible for the failure of insulin administration to rescue the histological effects described here within the timeline of the experiments.
We suggest that the survival effect (manifested as an increased time for apoptosis) is mediated by insulin signaling and cross-talk with the IGF-1 pathway, and that the antiapoptotic pathway (seen as a reduction in the rate of apoptosis) is manifested by modulating the turnover of the androgen receptor and the rate of nuclear depletion after castration. Our laboratory is currently engaged in dissecting these signaling pathways.
Testosterone deficiency compromises insulin production and insulin receptor expression in muscle, liver, and adipose tissue (Muthusamy et al, 2007). Together, the data reported in this study demonstrate the existence of cross-talk between insulin and androgens, confirming, at least in part, the working hypothesis that endocrine hormones modulate the effects of androgens on the prostate gland. Working out this hypothesis seems important because the results might correlate aging, obesity, and diabetes with prostate physiology. The findings presented here are relevant because they reinforce the idea that hyperinsulinemia, diabetes, or both are risk factors in prostate diseases (ie, prostate hyperplasia and cancer) and prognostic factors for the resurgence of androgen-independent prostate cancer after orchiectomy.
Acknowledgments
This study was part of the MSc thesis of D.M.D.
Footnotes
Funding from FAPESP and CNPq is acknowledged. D.M.D. was a recipient of CAPES and CNPq fellowships.
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± standard deviation (n = 4).
Little significant variation was observed in body weight during the
experiment. (B) Variation in VP weight in response to castration in the
3 experimental groups (nondiabetic, diabetic, and insulin-treated diabetic
animals). Values correspond to the 
