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Research Articles |
Authors' Affiliations: 1 Science Park-Research Division, The University of Texas M. D. Anderson Cancer Center, Smithville, Texas; 2 Division of Nutritional Sciences, The University of Texas at Austin, Austin, Texas; and 3 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Requests for reprints: John DiGiovanni, Department of Carcinogenesis, Science Park-Research Division, The University of Texas M. D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9414; Fax: 512-237-2522; E-mail: jdigiova{at}mdanderson.org, or Stephen D. Hursting, Division of Nutritional Sciences, The University of Texas at Austin, One University Station, Austin, TX 78712. Phone: 512-471-2809; Fax: 512-471-5630; E-mail: shursting{at}mail.utexas.edu.
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Abstract |
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In experimental model systems, calorie restriction (CR), which induces negative energy balance and prevents or reverses obesity, is arguably the most potent dietary-based intervention for preventing cancer (3). CR has been shown to inhibit formation of spontaneous neoplasias in several knockout and transgenic mouse models, to suppress tumor growth in tumor transplant models, and to inhibit radiation-induced and chemically induced carcinogenesis in a variety of rodent cancer models (3-8). In contrast, tumor development is generally enhanced in rodent models of diet-induced obesity (DIO; refs. 5, 9-12). Despite the well-established anticancer effects of CR, no mechanism of inhibition has been clearly identified.
We and others have previously established that reductions in circulating insulin-like growth factor-I (IGF-I) are associated with the anticancer effects of CR in specific model systems (3). In addition, with the exception of a short-term IGF-I infusion study (13), restoration of circulating IGF-I levels in mice on CR diets has been shown to ablate many of the antitumor effects of CR in multiple tumor models (14, 15). In contrast, DIO can lead to insulin resistance and increased circulating IGF-I (5). We have also reported that A-Zip/F-1 mice, which lack white adipose tissue but are diabetic, display elevated IGF-I levels and, like obese mice, are highly susceptible to several types of epithelial cancers (16). Taken together, these data suggest a critical role for circulating levels of growth factors, such as IGF-I, in the regulation of dietary energy balance effects on carcinogenesis.
The possible involvement of IGF-I in cancer was first suspected when in vitro studies consistently showed that IGF-I enhanced the growth of a variety of cancer cell lines (17, 18). A role for IGF-I in cancer was further confirmed when human breast (19), colon (20), and lung tumors (21) were shown to overexpress IGF-I, the IGF-I receptor (IGF-IR), or both. Additional epidemiologic evidence identified an association between elevated circulating levels of IGF-I and increased risk of several epithelial cancers in humans (22, 23). Increased signaling through the IGF-IR leads to enhanced suppression of apoptosis, increased mitogenesis, and cell cycle progression (24, 25).
Evidence suggests that many of these IGF-I-related effects on cellular growth and metabolism involve signaling through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway (26-28), one of the most commonly altered pathways in human tumors (29-33). For example, overexpression of IGF-I in the epidermis of HK1.IGF-I and BK5.IGF-I transgenic mice led to a dramatic increase in sensitivity to tumor development using the two-stage skin carcinogenesis protocol, a well-established model for epithelial carcinogenesis (26, 34). Thus, elevated tissue levels of IGF-I and enhanced signaling through the IGF-IR led to enhanced susceptibility to tumorigenesis. The ability of elevated tissue IGF-I levels to promote skin tumors is due, at least in part, to activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, which has been shown to regulate epithelial cell proliferation (28, 35, 36). When either wild-type or myristoylated mouse Akt was overexpressed in epidermal basal cells under control of the BK5 promoter, susceptibility to two-stage skin carcinogenesis was further enhanced (36). Western blot analyses performed on protein lysates prepared from either Akt transgenic mouse model showed enhanced signaling through the Akt/mTOR pathways, with heightened activation of downstream effectors of both Akt and mTOR (36).
A similar pattern of increased activation of Akt/mTOR signaling in the skin epidermis of the fatless but diabetic A-Zip/F-1 mice was associated with the increased skin and mammary tumor susceptibility observed in these mice (16). Collectively, these data further support the hypothesis that elevated IGF-IR signaling and, in particular, activation of the Akt/mTOR pathways may contribute to increased susceptibility to epithelial carcinogenesis. AMP-activated protein kinase (AMPK), which acts as a nutrient-dependent regulator of mTOR (37), may also be involved. During nutrient deprivation conditions, AMPK can be activated by upstream kinases and function to repress activation of mTOR, thus reducing cellular energy expenditure (38-44).
In the present study, we used well-established dietary regimens to induce positive and negative energy balance in mice to further explore potential mechanisms underlying the energy balance and cancer link (5, 45-48). Biochemical analyses were performed on multiple epithelial tissues from three commonly used mouse strains to determine diet-induced changes in steady-state cell signaling. The results indicate that dietary energy balance manipulation modulates signaling through the Akt and mTOR pathways in all three tissues examined (i.e., epidermis, liver, and dorsolateral prostate). Furthermore, modulation of these signaling pathways seemed to be primarily mediated via alterations in signaling through the IGF-IR and the epidermal growth factor receptor (EGFR). Finally, phosphorylation of AMPK in response to either a positive or a negative energy balance seemed to be tissue dependent. Overall, the current data identify the Akt/mTOR signaling pathways as potential targets for cancer prevention and, in particular, for prevention of obesity-related cancers.
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Materials and Methods |
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Animals
Male FVB/N and C57BL/6 mice (30 per genetic background, 3-4 wk of age) were purchased from National Cancer Institute and singly housed for the duration of the experiment. Thirty-two female ICR mice (3-4 wk of age) were purchased from Harlan Teklad and group-housed for the duration of the experiment.
Diet regimens
All diets were purchased in pellet form from Research Diets, Inc. On arrival, mice were placed on a 10 kcal% fat (control) diet (AIN-76A semipurifed diet, fed ad libitum; diet D12450B) for a 1-wk equilibration period and then randomized into three dietary treatment groups (10 mice per group): (a) control diet (10 kcal% fat), fed ad libitum; (b) DIO (high-fat) diet (60 kcal% fat; D12492), fed ad libitum; and (c) 30% CR diet (D03020702). These diets have previously been described (4). For the study conducted in ICR mice, female mice were maintained on the diets described above (eight mice per group) and an additional dietary treatment was introduced: 15% CR diet (D03020703). Mice receiving either CR diet were given a daily aliquot equivalent to either 70% or 85% of the daily amount of total energy consumed by the control diet group. Both CR diets were adjusted to provide 100% of all vitamins, minerals, fatty acids, and amino acids relative to the control group. Under group-housing conditions, mice receiving the 30% CR diet were placed in a cage divider system for 2 h and allowed to consume their daily food allotment. Average body mass and food consumption were determined weekly for each dietary treatment group. With the exception of ICR mice, which received their diet regimens for 15 wk, all mice were maintained on their diet regimens for 17 wk. All groups were terminated by CO2 asphyxiation and tissues and blood were collected, processed, and stored as described below.
Preparation of protein lysate
Immediately after the mice were terminated, the dorsal skin was shaved and then a depilatory agent was applied for 30 s and then removed. The skin was excised and the epidermal tissue was scraped from the excised skin using a razor blade into prepared lysis buffer [0.5% Triton X-100, 1% NP40, 10% glycerol, 50 mmol/L HEPES (pH 7.5), 150 nmol/L NaCl, 1 mmol/L EGTA, 1.5 mmol/L MgCl2, 10% Sigma inhibitor cocktail, 10% phosphatase inhibitor cocktail I, and 10% phosphatase inhibitor cocktail II] and homogenized using an 18-guage needle. Epidermal scrapings from all mice in each dietary group were pooled (10 mice per group for FVB/N and C57BL/6 and 8 mice per group for ICR). The liver and dorsolateral prostate were removed from FVB/N and C57BL/6 mice, frozen in liquid nitrogen, and then ground with a mortar and pestle. Once in powder form, liver and prostate tissues were homogenized using an 18-guage needle in the lysis buffer described above. Again, both liver and prostate tissues from 10 mice were pooled per dietary group. The epidermal, liver, and prostate homogenates were then centrifuged at 14,000 rpm for 15 min, and the supernatant was aliquoted for use for Western blot analysis.
Western blot analysis
For analysis of receptor tyrosine kinase activation and phosphorylation of Akt/mTOR signaling molecules, 100 µg of epidermal lysate were electrophoresed in 4% to 15% SDS-polyacrylamide gels according to the method of Laemmli (49). The separated proteins were then electrophoretically transferred onto nitrocellulose membranes and blocked with 5% bovine serum albumin in TBS with 1% Tween 20 (TTBS). Blots were then incubated overnight with the antibodies described above in 5% bovine serum albumin in TTBS. Blots were washed with TTBS thrice for 15 min each and then incubated in antirabbit and anti-mouse secondary antibody in 5% bovine serum albumin in TTBS for 2 h. Blots were washed again with TTBS thrice for 15 min each, and then the protein bands were visualized by enhanced chemiluminescence (Pierce). Protein quantification was then determined using an alpha imager system. Each blot was repeated, producing nearly identical results.
Serum IGF-I analysis
Blood was collected by cardiac puncture immediately following CO2 asphyxiation (10 mice per diet group for FVB/N and C57BL/6 and 8 mice per diet group for ICR), allowed to sit at room temperature for 2 h, and then spun at 7,500 rpm for 7 min. Supernatant was then collected and spun again under the same conditions. The final supernatant was collected, flash frozen in liquid nitrogen, and stored at –80°C until analysis. Total mouse serum IGF-I concentration was then measured using a 25-µL sample with a RIA kit (Diagnostic Systems Laboratories, Inc.).
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Results |
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Serum analyses of total IGF-I were done to further characterize the effects of dietary manipulation on circulating IGF-I levels. As shown in Tables 1 and 2, serum IGF-I levels were significantly different among the diet groups in both FVB/N and C57BL/6 mice, with the greatest differences occurring between mice on the CR and DIO regimens. FVB/N mice on the CR diet exhibited a 55% reduction in total circulating IGF-I levels relative to FVB/N mice on the DIO diet, whereas C57BL/6 mice on the CR diet exhibited a 79% reduction in total circulating IGF-I levels relative to C57BL/6 mice on the DIO diet. These data, in combination with the weight distribution data, indicate that both FVB/N and C57BL/6 mice respond similarly to dietary energy balance manipulation.
Effect of dietary energy balance manipulation on the activation of Akt and mTOR in multiple epithelial tissues
In an effort to explore the signaling pathways involved in the dietary energy balance effects on epithelial carcinogenesis, we carried out Western blot analyses on protein lysates prepared from pooled epidermal, hepatic, and dorsolateral prostate tissues collected from FVB/N and C57BL/6 male mice maintained on the different diets as described above (tissue samples were pooled from 10 mice per diet group). As shown in Fig. 1, CR reduced, whereas the DIO diet increased, activation (as assessed by phosphorylation status) of both Akt and mTOR in all three epithelial tissues examined, relative to mice maintained on the control diet. These data show that dietary energy balance manipulation altered steady-state signaling to Akt and mTOR in the epidermis, liver, and dorsolateral prostate.
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Role of AMPK in the regulation of mTOR signaling
To explore the role of AMPK in the regulation of mTOR signaling in tissues from mice on the various diets, we carried out Western blot analyses to examine its activation status. As shown in Fig. 3, activation of AMPK, as measured by phosphorylation at Thr172, was similar in protein lysates from epidermis and prostate across all three diets. This was also true for both genetic backgrounds (i.e., FVB/N and C57BL/6). In contrast, phosphorylation of AMPK was elevated in protein lysates from liver of mice on the CR diet relative to mice on either the control or the DIO diet. Again, this was true for either genetic background. These results suggest that the effects of dietary energy balance modulation on AMPK signaling may be tissue dependent. The lack of dietary energy effects on epidermal AMPK was confirmed in subsequent studies using ICR mice (see below).
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Discussion |
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As noted in the introduction, evidence in the literature suggests a role for circulating IGF-I in modulating tumorigenesis (50, 51). Further evidence comes from using liver IGF-I–deficient mice (50-53). In this regard, deletion of the IGF-I gene in hepatocytes leads to a 75% reduction in circulating IGF-I levels (53), allowing for examination of the effect of reduced circulating IGF-I on carcinogenesis in multiple tissues in the absence of dietary manipulation. This LID mouse model has been used to study the effect of reduced circulating IGF-I on mammary tumor development with both chemical induction and transgenic approaches (52). Additional studies were conducted to examine the effect of reduced circulating IGF-I levels on growth and metastasis of Colon 38 adenocarcinoma cells following orthotopic transplantation (50). Both of these studies showed significant effects of reduced circulating IGF-I on tumor growth (inhibition) although the underlying mechanism(s) for these effects was not explored.
When serum IGF-I levels were restored in LID mice by recombinant human IGF-I supplementation, the inhibitory effects on colon cancer were abolished. More recently, we have examined the effect of reductions in circulating IGF-I on two-stage skin carcinogenesis, a well-established model for epithelial carcinogenesis (51). In these studies, LID mice were highly resistant to two-stage skin carcinogenesis. Mechanistic studies showed that LID mice had a reduced responsiveness to 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced epidermal hyperplasia and epidermal proliferation. Furthermore, biochemical studies showed that LID mice exhibited reduced activation of both the IGF-IR and EGFR, as well as downstream signaling through Akt and mTOR, following TPA treatment compared with wild-type mice. These data suggest a possible mechanism whereby reduced circulating IGF-I attenuates activation of Akt and mTOR, thus reducing the response of epidermal cells to tumor promotion. Furthermore, these findings support the hypothesis that reduced circulating IGF-I levels contribute to the anticancer effects of CR in multiple tissues.
In an effort to determine if modulation of circulating IGF-I levels through manipulation of dietary energy balance led to altered Akt/mTOR signaling, as suggested by the studies with LID mice, we examined the status of critical signaling molecules in the Akt and mTOR pathways in the epidermis, liver, and dorsolateral prostate from both FVB/N and C57BL/6 mice maintained on disparate dietary regimens. As shown in Fig. 1, positive energy balance enhanced, whereas negative energy balance inhibited, activation of both Akt and mTOR, regardless of tissue or genetic background. Furthermore, the inhibitory effects of CR were confirmed when phosphorylation status or protein level of downstream effectors of both Akt and mTOR was examined. Of particular interest is the effect of dietary energy balance on cyclin D1 levels across the three tissues. In general, cyclin D1 levels were reduced by CR relative to the control and DIO diet groups across the three tissues.
These findings are consistent with earlier studies linking reduced levels of cyclin D1 to energy restriction in both a mouse mammary cell line and in uninvolved, premalignant and malignant rat mammary tissues following treatment with methylnitrosourea (54, 55). Cyclin D1 levels are known to be regulated downstream of both Akt and mTOR (56-59) as well as downstream of other signaling pathways activated by growth factor receptor signaling (60-62). As can be seen in Fig. 2, phosphorylation of GSK-3β, which is immediately downstream of Akt, was modulated by dietary energy balance in all three tissues in a manner consistent with Akt phosphorylation status and cyclin D1 levels. The importance of cyclin D1 in epithelial carcinogenesis in mouse epidermis has been shown in a number of studies with transgenic mouse models (63-65) as well as cyclin D1 knockout mice (66).
Further Western blot analyses were performed to determine if the effects of dietary energy balance on steady-state signaling to the mTOR pathway were controlled by AMPK, a known upstream nutrient-sensing regulator of mTOR signaling (37). As shown in Fig. 3, AMPK activation was not affected by dietary manipulation in protein lysates from either the epidermis or the dorsolateral prostate; however, CR led to activation of AMPK in the liver. Notably, these results in the liver differ from previously published data in which hepatic AMPK phosphorylation was found to be unchanged in C57BL/6 male mice in response to CR (67). There are several differences, however, between the study by Gonzalez et al. (67) and our current study: (a) mice were maintained on a 35% CR dietary regimen; (b) CR mice were fed on an alternate-day feeding regimen; and (c) food consumption of control mice was actually restricted by 10%. In our current study, dietary energy balance manipulation seemed to alter signaling to mTOR in epidermis and prostate in a manner independent of AMPK activation, although in liver AMPK does seem to play a role. Further work will be necessary to explore how changes in dietary energy balance affect AMPK activity in vivo in specific tissues.
The data from our recent studies using LID mice suggested that reduced circulating IGF-I levels affected signaling through both the IGF-IR and EGFR in epidermis of mice during tumor promotion (51). Therefore, Western blot analyses were carried out on epidermal protein lysates from mice maintained on control, DIO, and CR diets. For these studies, we used female ICR mice and also included a 15% CR group. Notably, we found that dietary energy balance affected signaling through the IGF-IR and EGFR in epidermis, consistent with its effects on downstream signaling (see Figs. 1A, 2A, and 4). This effect on receptor tyrosine kinase activation is strikingly similar to the effects seen in LID mice and may explain, in part, the mechanism by which dietary energy balance alters signaling to Akt and mTOR as well as other downstream signaling pathways (Erk1/2 and c-Src). Collectively, these data suggest that serum IGF-I levels may regulate signaling through both the IGF-IR and EGFR possibly by modulating cross talk between these two cell-surface receptor tyrosine kinases. In support of this latter idea, we previously reported the development of HK1.IGF-I transgenic mice wherein expression of IGF-I is targeted to epidermis using the human keratin 1 (HK1) promoter (34, 68). Following treatment with TPA, there was a significant increase in EGFR activation in epidermis of HK1.IGF-I transgenic mice compared with wild-type mice. These data suggested that tissue levels of IGF-I and, presumably, activation state of the IGF-IR could influence the overall activation level of the EGFR. A number of mechanisms have recently been proposed whereby cross talk between the EGFR and IGF-IR may occur (69-73). Current experiments are exploring possible mechanisms whereby circulating IGF-I levels, as modulated by dietary energy balance manipulation, influence cross talk between the IGF-IR and the EGFR.
In conclusion, we have shown that dietary energy balance modulation alters signaling through the Akt and mTOR pathways in multiple epithelial tissues of mice, regardless of genetic background. The mechanism for the effect of dietary energy balance on signaling to the Akt and mTOR pathways seems, at least in part, to be mediated by changes in serum IGF-I levels, which then alters signaling through the IGF-IR and EGFR. The role of AMPK in regulating mTOR signaling in vivo during energy balance modulation is less clear and may be highly tissue specific. Further work using in vivo model systems will be important in this regard. Earlier work reported by Birt and colleagues showed an attenuation of TPA-induced activator protein-1 activation (74-76) and Erk activation in mice on 40% CR diets. We found that dietary energy balance also modulated steady-state activation of both Erk1/2 and c-Src (Fig. 4). Both of these signaling pathways are known to be downstream of receptor tyrosine kinases such as the IGF-IR and EGFR (60-62).
Finally, Xie et al. (77) reported reduced phosphatidylinositol 3-kinase and ras signaling in response to TPA in skin of SENCAR mice on CR diets as compared with controls. In this study, phosphorylation of Akt in epidermis following TPA treatment was reduced by CR and to a greater extent by CR plus exercise. Collectively, these published findings and the data currently presented support the hypothesis that dietary energy balance modulates signaling downstream of cell-surface receptors. A summary of our current results and its implication for epithelial carcinogenesis is shown in Fig. 6. The observation that dietary energy balance manipulation leads to altered signaling through both Akt and mTOR in multiple epithelial tissues via modulation of cell-surface receptor tyrosine kinase signaling is novel. These findings provide the basis for future translational studies targeting the Akt/mTOR pathway via combinations of lifestyle (i.e., moderate calorie restriction regimens) and pharmacologic approaches for the prevention and control of obesity-related epithelial cancers in humans.
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Disclosure of Potential Conflicts of Interest |
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Footnotes |
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Received for publication January 30, 2008.
Revision received February 26, 2008.
Accepted February 26, 2008
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References |
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) enhances, whereas CR (
) decreases, phosphorylation of Akt, mTOR, and their downstream effectors. Of particular importance is the differential effect of dietary energy balance on cyclin D1 levels. Signaling downstream of both Akt and mTOR has been shown to regulate cyclin D1. Further analysis of receptor tyrosine kinase downstream signaling shows that dietary energy balance differentially regulates activation of both Erk and c-Src, which subsequently regulate cyclin D1. Modulation of the Akt and mTOR signaling pathways, in combination with altered signaling through other growth factor signaling pathways, provides a mechanistic explanation for the effect of dietary energy balance on epithelial carcinogenesis.