Relationship Between Aerobic Fitness,the Serum IGF-1 Profiles of Healthy Young Adult African American Males,and Growth of Prostate Cancer Cells

Abstract

The growth of prostate tumors is mediated by the bioavailability of androgens and insulin-like growth factors. This study tested the hypothesis that healthy young adult African American men exhibiting low aerobic capacity (fitness) have serum insulin-like growth Factor-1 (IGF-1) and testosterone levels that promote growth of prostate cancer cells. A cross-sectional data research design was used to study groups of 18- to 26-year-old healthy men exhibiting low and moderate aerobic fitness, based on their peak oxygen consumption (VO_2peak). The individual serum levels of IGF-1, IGF-1 binding protein-3 (IGFBP-3), and testosterone were measured. In vitro growth of androgen-dependent LNCaP prostate tumor cells was measured after incubation in culture medium fortified with each subject’s serum. Aerobic capacity was significantly greater in the moderate-fitness group than in the low-fitness group without an intergroup difference in body mass index. The serum IGF-1 concentration was significantly higher in the low-fitness group in the absence of an intergroup difference in serum testosterone. The serum IGFBP-3 concentration was significantly lower in the low-fitness group. Prostate tumor cell growth was significantly greater in the cultures incubated in media containing the sera of the low-fitness group than in the sera of the moderate-fitness group. These findings suggest that moderate aerobic fitness in young adults may decrease the circulating levels of free IGF-1 and lower the potential to support growth of prostate cancer cells.

Keywords

prostate cancer aerobic capacity IGF-1 IGFBP-3 testosterone African Americans

Introduction

Prostate cancer is relatively indolent in most men, including the elderly. However, one out of six prostate cancer patients presents with an aggressive form of disease that is highly metastatic and a frequently fatal disease. As a consequence, prostate cancer is the leading cause of cancer-related death in men (Kwabi-Addo et al., 2007) and its prevalence in African American men is the highest in the world (Peters & Armstrong, 2005). Prostate cancer presents at a younger age and is more virulent in Blacks than in Whites (Kheirandish & Chinegwundoh, 2011), and individuals of African American ethnicity are reported to exhibit a higher risk of prostate cancer-specific mortality than European Americans (Mahal et al., 2014). Moderate exercise has been associated with a lower risk of prostate cancer and, in men with cancer, lower grade disease (Antonelli et al., 2009). Aerobic exercise did not counteract the growth-promoting effects of a high-fat diet on growth of human prostate cell xenografts in mice, suggesting that diet may be more influential in prostate cancer cell growth than exercise (Vandersluis et al., 2013). These findings suggest a need to determine whether healthy young-adult African American men possess factors that promote growth of prostate cancer cells. Variations in genetic endowment and in a number of environmental and lifestyle factors may explain this apparent health disparity (Powell, 2007). Insulin-like growth factor (IGF) and testosterone are reported to promote the growth of prostate cancers (Nam et al., 2005; Parsons et al., 2005; Severi et al., 2006). Young adult and middle-age African American men have been reported to have higher plasma testosterone levels than European American men (Ellis & Nyborg, 1992; Ross et al., 1986). Lifestyle is thought to play a role in prostate cancer by a number of mechanisms including physical inactivity, promoting low aerobic fitness (Darlington, Kreiger, Lightfoot, Purdham, & Sass-Kortsak, 2007; Giovannucci, Liu, Leitzmann, Stampfer, & Willett, 2005; Patel et al., 2005; Sass-Kortsak, Purdham, Kreiger, Darlington, & Lightfoot, 2007) and ingested agents, such as lycopene present in products derived from tomato (Darlington et al., 2007), the carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine associated with consumption of grilled red meat (Tang et al., 2007) or nonsteroidal anti-inflammatory drugs (Harris, Beebe-Donk, & Alshafie, 2007). Physical activity is reported to decrease insulin-like growth factor-1 (IGF-1) levels in the sera of elderly men and inhibit in vitro growth of prostate cells incubated in media fortified with such sera (Ngo, Barnard, Tymchuk, Cohen, & Aronson, 2002). The present study tests the hypothesis that the sera of physically inactive young adult African American men having lower aerobic fitness contain higher circulating levels of IGF-1 and testosterone, which may promote the growth of prostate cancer cells.

Method

Subjects

The study was approved by the Howard University Institutional Review Board for Human Participants. Subjects were recruited using a flyer requesting volunteers for a study on prostate cancer cell growth and were informed about the experimental procedure and purpose of the study, and written informed consent was obtained. Thirty healthy college-aged young adult African American males were screened for lifestyle of physical activity using the Godin Leisure-Time Physical Activity Questionnaire (Godin & Shephard, 1985) and level of aerobic fitness further assessed by the method of measuring peak oxygen uptake (VO_2peak). Thirteen subjects were dropped because of failure to complete the questionnaire or VO_2peak test. The remaining 17 subjects were grouped as follows: 9 subjects engaging in some form of dynamic exercise 3 days/week for 30 minutes per session with a VO_2peak > 40 mL/kg/min defined a moderate aerobic fitness group and 8 subjects with a sedentary lifestyle involving <1 day/week of physical activity with a VO_2peak ≤ 35 mL/kg/min defined a low-fitness group. The VO_2peak values used for defining the aerobic fitness levels were adopted from normative population data (Shvartz & Reibold, 1990).

VO_2peak and Serum Hormone Measurements

Experimental testing consisted of two laboratory visits. On the first visit, subjects were instructed to avoid physical activity and ingestion of food for 3 hours before testing. Body height and weight were measured using standard laboratory procedures. To assess VO_2peak, progressive exercise testing was performed on an electronically braked cycle ergometer (SensorMedics 800S, Yorba Linda, CA). After a 5-minute warm-up with no load, subjects completed a graded exercise test to measure VO_2peak (defined as the highest 60 s average). Power output began at 25 W and increased 25 W every 2 minutes until volitional fatigue. Oxygen consumption, carbon dioxide production, minute ventilation, and respiratory quotient were determined by indirect calorimetry using a Physiodyne Max II Metabolic Measurement System (Physio-Dyne, Quoge, NY). Heart rate was monitored continuously using a Polar® Precision monitor (Polar Electro Inc., Port Washington, NY). The second laboratory visit was used to obtain a venous blood sample after a 12-hour fast and 24 hours of no physical activity. Fasting blood samples were obtained from the subjects in the morning, allowed to clot, and then were centrifuged to obtain serum. The serum was frozen and stored at −80°C until used for analyses. Serum samples were analyzed in duplicate for IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and testosterone using ELISA 96-well kits from ALPCO Diagnostic (Salem, NH).

Cell Culture

Androgen-dependent LNCaP prostate tumor cells were obtained from American Type Culture Collection (Manassas, VA). The cells were maintained by culturing in RPMI 1640 medium with 2 mM l-glutamine adjusted to contain 10% fetal bovine serum, 4.5 g/L glucose, 10 mM HEPES buffer, 1.0 mM sodium pyruvate, 100 U/mL penicillin, and 100 µg/mL streptomycin. The cell cultures were maintained at 37°C in a humidified atmosphere air containing 5% carbon dioxide. For testing the growth promoting effects of sera from different individuals, LNCaP cells were seeded in sterile 96-well plates at an initial density of 1 × 10⁴ cells per well and incubated overnight in medium containing 10% fetal bovine serum. Medium containing fetal bovine serum was replaced with medium supplemented with human serum obtained from the different individuals. For this purpose, each subject’s serum (20 µL) was added to 180 µL of serum-free RPMI 1640 medium per well. After 48 hours of incubation at 37°C, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium colorimetric assay (MTT assay; Sigma, St. Louis, MO) was performed to estimate cell proliferation based on the reduction of the tetrazolium dye by viable cells. After removing the old medium, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide solution (100 µlL; 0.5 mg/mL) in complete RPMI 1640 medium (phenol red free) was added. Following 3 hours of incubation at 37°C, the absorbance at 560 nm wavelength was determined using a multiwell spectrophotometer (BIO-RAD, Hercules, CA). Each subject’s serum sample was tested in four separate wells, with the mean value used for relative cell growth analysis.

Statistical Analysis

All values are reported as mean ± standard error. A one-way ANOVA was used to examine the associations between aerobic fitness and the dependent measurements of serum IGF-1, IGFBP-3, and testosterone concentrations. The level of significance was set at p < .05. Statistical analyses were performed using commercial statistical software (Statsoft, Tulsa, OK).

Results

Characteristics of the study subjects are presented in Table 1. Body weight and body mass index tended to be higher in the low aerobic fitness group than in the moderate aerobic fitness group, but the difference was not statistically significant. The moderate aerobic fitness group possessed significantly higher VO_2peak (47.5 ± 2.9 vs. 31.0 ± 1.7 mL/kg/min, p < .05) and peak power output values (244.4 ± 16.5 vs. 182.5 ± 12.2 W, p < .05) compared with the corresponding values for the low aerobic fitness group. Intergroup differences in age, height, heart rate, blood pressure, and respiratory quotient values were not significant.

Table 1.

Characteristics of the Study Group.

Variable	Low-fitness group (n = 8)	Moderate-fitness group (n = 9)
Age (years)	19.8 ± 0.5	20.1 ± 0.3
Height (cm)	172.8 ± 3.3	172.8 ± 3.3
Weight (kg)	82.7 ± 6.0	75.4 ± 4.7
Body mass index (kg/m²)	28.2 ± 3.4	25.8 ± 2.2
Heart rate at rest (beats/minute)	83.1 ± 4.6	80.3 ± 5.4
Heart rate peak (beats/minute)	183.3 ± 2.4	187.4 ± 2.9
VO_2peak (mL/kg/min)	31.0 ± 1.7	47.5 ± 2.9*

Note. VO_2peak = peak oxygen consumption.

Intergroup difference significant at p < .05.

Results of the human serum–stimulated growth assay are depicted in Figure 1. Relative growth of the LNCaP cells incubated in the sera of the moderate-fitness group was significantly less than that for cells incubated in the sera of the low-fitness group (134.5 ± 8.1 vs. 62.8 ± 9.3%, p < .05). The difference in fasting serum testosterone concentration of the low-fitness and moderate-fitness groups was not significant (p > .1; Figure 2).

Figure 1.

LNCaP tumor cell growth (mean ± SE) cultured in sera from groups of healthy young adult African American males characterized by low and moderate aerobic fitness. *Intergroup difference significant at p < .05.

Figure 2.

Testosterone concentrations (mean ± SE) in serum samples from groups of healthy young adult African American males characterized by low and moderate aerobic fitness. Intergroup difference not significant (p > 0.1).

The fasting serum IGF-1 concentration was 26% lower (240.5 ± 16.3 vs. 319.1 ± 14.4 ng/mL) for the moderate-fitness group than for the low-fitness group (p < .05; Figure 3). The fasting serum IGFBP-3 concentration was lower for the low-fitness group than for the moderate-fitness group (p < .05; Figure 4).

Figure 3.

Insulin-like growth factor-1 (IGF-1) concentrations (mean ± SE) in serum samples from groups of healthy adult African American males characterized by low and moderate aerobic fitness. *Intergroup difference significant at p < .05.

Figure 4.

Insulin-like growth factor binding protein-3 (IGFBP-3) concentrations (mean ± SE) in serum samples from groups of healthy young adult African American males characterized by low and moderate aerobic fitness. *Intergroup difference significant at p < .05.

Discussion

The purpose of the present study was to determine if a lifestyle promoting aerobic fitness has the potential to produce physiological adaptations that may inhibit the in vitro growth of androgen-sensitive prostate cancer cells. The main finding of this study is that the sera of healthy young men exhibiting a normal (moderate) aerobic capacity contain a significantly lower concentration of IGF-1 accompanied by a significantly higher concentration of IGFBP-3 and produce significantly less serum-supported growth of prostate cancer cells than the sera of healthy young men exhibiting lower aerobic capacity. Previous studies have reported that the sera of elderly men subjected to a regimen of physical activity contain a lower concentration of IGF-1 than the sera of a similar group of physically inactive men; moreover, the in vitro growth of LNCaP prostate cancer cells was inhibited by such sera (Barnard, Aronson, Tymchuk, & Ngo, 2002; Barnard, Leung, Aronson, Cohen, & Golding, 2007; Barnard, Ngo, Leung, Aronson, & Golding, 2003; Leung, Aronson, Ngo, Golding, & Barnard, 2004; Ngo, Leung, Barnard, Cohen, & Aronson, 2003). To our knowledge, the present study is the first to identify an association between aerobic capacity and inhibition of prostate cancer cell growth in media supplemented with human sera from healthy young adult African American men. African American men constitute an ethnic group destined to have the highest incidence of prostate cancer among the U.S. population at large. Worldwide, the highest incident rates of prostate cancer are reported in developed countries and Black men are identified to be at greater risk, and present with prostate cancer at a younger age, than their White counterparts (Kheirandish & Chinegwundoh, 2011). There is no reason to believe that the finding of the present study suggesting that sera of Black men with higher aerobic capacity may contain factors that produce more prostate cancer cell inhibition than those with low aerobic capacity, does not apply to all men, regardless of ethnicity. There is a report that suggests that exercise has a greater prostate cancer risk reduction potential in White than in Black men (Singh et al., 2013).

The IGF family has been implicated in cancer development and progression (Yu & Rohan, 2000). Insulin-like growth factors including IGF-1 are mitogens that regulate cell proliferation, differentiation, and apoptosis. IGFBP-3 is responsible for binding the majority of IGF-1 and decreasing its bioavailability. Laboratory studies have demonstrated strong mitogenic and anti-apoptotic activities toward a variety of cancer cells. Epidemiological studies also suggest that high levels of circulating IGF-1 and low levels of IGFBP-3 are associated with risk of prostate, breast, colon, and lung cancers (Pollak, Schernhammer, & Hankinson, 2004; Yu & Rohan, 2000). IGF-1 stimulates mitosis in normal as well as tumor cells, while inhibiting apoptosis of transformed and malignant cells. Studies of physical activity have suggested an effect on IGF-1. A systematic review of studies of physical activity on IGF-1 has led to conflicting findings that correlate physical activity with an increase, decrease, or no effect on IGF-1 levels (Pollak et al., 2004). It is reported that serum from individuals on an exercise regimen stimulated LNCaP tumor cell growth when tyrphostin was used to block the IGF-1 receptor in cells (Barnard et al., 2007). Our finding of less prostate tumor cell growth in cultures supplemented with sera of young men exhibiting moderate aerobic capacity than in cultures supplemented with sera of young men exhibiting less aerobic capacity may be explained by differences in circulating levels of IGF-1, which could be related to the IGF-1/IGFBP-3 concentration ratio in the two groups. If so, our findings for this population of healthy young adults may be important because a prominent hypothesis is that physical activity protects against cancer through reduced lifetime exposure to endogenous metabolic hormones (Campbell & McTiernan, 2007).

The addition of testosterone to serum cultures is known to increase the growth of androgen-dependent prostate cancer cells (Tymchuk, Barnard, Ngo, & Aronson, 2002) and is the rationale for androgen-deprivation therapy (Akaza et al., 2006). In the present study, despite the greater cell growth rate of the prostate tumor cells incubated in the serum of the less-fit group than in the serum of the moderately fit group, there was no intergroup difference in serum testosterone concentration. A similar finding, that serum testosterone was not affected by physical activity, has been reported for a group of middle-aged and elderly men (Hawkins et al., 2008; Nicklas, Ryan, & Treuth, 1995). The problem of relating physical activity or fitness to prostate cancer risk is complex, as identified by the unexpected finding of a longitudinal study that reported a positive association between physical fitness and prostate cancer (Byun et al., 2011). The subjects of this study were from a health-savvy population subjected to treadmill testing and a mail-in health survey. Differential results were obtained for men enrolled during the pre–prostate-specific antigen screening era, and those afterwards. Our experimental approach of incubating serum from subjects categorized by fitness according to aerobic capacity and observing prostate cancer cell growth in vitro is a novel experimental design that avoids such bias.

Study Limitations

Our study employed an experimental model combining serum from human subjects and cultured cancer cells. The small number of subjects and several other factors must be recognized as limitations. One limitation is our exclusion of ethnicities other than African American. This exclusion might lead one to infer that our results are applicable only to Blacks. Another limitation is that concentrations of hormones and growth factors in serum may not be a true or accurate index of growth factor levels in prostate tissue or in prostate tumors (Goldenberg, Koupparis, & Robinson, 2011). In vitro assays of cell proliferation in media supplemented with human serum also may not correlate with the actual proliferation potential of tumor cells in vivo as judged by measuring markers of cell proliferation such as ki-67 (Michalski & Chen, 2010). A report that prostate-specific antigen has proteolytic activity that can degrade IGFBPs, (Maeda et al., 2009) may suggest a need for prostate-specific antigen measurements. Precisely how IGFBPs affect circulating levels of IGF-1 is also, largely, unknown. This model was used because it facilitated the study of hormones and growth factors from sera of healthy subjects exhibiting different levels of VO_2peak, a reliable measure of aerobic fitness. Prostate cancer develops over many years, even decades, during which time growth factors in serum promote the proliferation of both normal and aberrant, mutant and/or malignant, cells. Our subjects were young adult males and one might argue that prostate cancer is seldom seen in young men; however, evidence is emerging that the roots of prostate cancer may be planted in young adulthood, adolescence, or even childhood (Aarestrup, Gamborg, Cook, Sørensen, & Baker, 2014). In that regard, the present study draws attention to the important, yet unresolved, issue as to whether regular aerobic exercise in early adulthood inhibits growth of prostate cancer cells sufficiently to protect against this common cancer in older men.

Conclusion

In summary, our finding that the serum of young adult African American men with moderate aerobic fitness produced less in vitro growth of prostate cancer cells than the serum of a similar group of subjects possessing low aerobic fitness suggests that a lifestyle incorporating physical activity may translate to inhibiting the evolution of prostate cancer.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work supported in part by NIH/NCRR/RCMI Grant No. 2G12RR003048.

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Relationship Between Aerobic Fitness,the Serum IGF-1 Profiles of Healthy Young Adult African American Males,and Growth of Prostate Cancer Cells

Abstract

Keywords

Introduction

Method

Subjects

VO2peak and Serum Hormone Measurements

Cell Culture

Statistical Analysis

Results

Discussion

Study Limitations

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References

VO_2peak and Serum Hormone Measurements