Role of Testosterone, Estradiol, and Insulin in Diet- and Exercise-Induced Reductions in Serum-Stimulated Prostate Cancer Cell Growth In Vitro

Abstract

Prostate cancer risk is associated with a high-fat diet and a sedentary lifestyle. Placing men on a low-fat diet-and-exercise intervention reduces serum hormones, including estradiol, insulin, and free testosterone, that may play a role in prostate cancer growth. Eight men participated in a low-fat diet-and-exercise program for a mean of 14.2 yr, and LNCaP cell growth in culture was measured in medium supplemented with 10% of each subject's serum as well as with testosterone, estradiol, and insulin added singly or in combination. These results were compared in the fetal bovine serum (FBS)-stimulated growth and cell growth in serum obtained from a control group of 14 overweight men. In separate tissue culture experiments, LNCaP and PC-3 cell growth was also measured in response to the addition of testosterone, estradiol, or insulin to steroid-stripped FBS. LNCaP cell growth in medium with subject serum was 40% less than in FBS-stimulated medium and 49% less than in medium with serum from control, overweight men. Addition of testosterone, estradiol, and insulin to serum from diet-and-exercise subjects significantly stimulated LNCaP cell growth in vitro but accounted for only about half of the difference between the control and diet-and-exercise subjects. Thus other serum changes must also account for the significant reduction in LNCaP cell growth observed using medium with serum from the diet-and-exercise subjects in the cell culture assay.

Effect of diet and exercise intervention on the growth of prostate epithelial cells

“…Insulin is a well-known anabolic hormone and may have a direct effect or may be acting through multiple indirect effects. In our studies with PCa cell lines we found that insulin had a direct growth-stimulating effect, but other factors related to the reduction in insulin in response to diet and exercise appeared to be more important 13,18,21 As testosterone is a recognized factor associated with BPH, we measured serum levels and found them to be low but unchanged in the 2-week samples. However, in men with hyperinsulinemia, free testosterone may be higher due to suppression of sex hormone-binding globulin (SHBG) production by the liver.…”

“…However, to our knowledge no one has demonstrated a direct effect of insulin on normal prostate tissue. A previous study from our laboratory 18 reported that insulin does stimulate the growth of the human LNCaP PCa cell line, and Polychronakos et al 19 reported that insulin stimulated the growth of rat PA-III adenocarcinoma cells.…”

The effect of physiological concentrations of sex hormones, insulin, and glucagon on growth of breast and prostate cells supplemented with unmodified human serum

“…Despite this conclusion, cell culture studies consistently associate physiological concentrations of the aforementioned hormones to prostate cancer development. These studies generally test the effect of different hormones at varying concentrations on the growth of breast and prostate cancer cells in the presence of a medium that is supplemented with charcoal-treated serum, usually from bovine sources (Tymchuk et al 2002;Arnold et al 2005Arnold et al , 2007. Charcoaltreated serum (CTS) is devoid of steroid hormones (Thermo Fisher Scientific 2009) and is, therefore, crucial for determining how cells react to a specific concentration of one or a combination of hormones.…”

Potential for prostate cancer prevention through physical activity

“…Normally, the physiological benefits of starting an exercise program take 8-12 weeks to manifest. But, if change in LNCaP cell growth can be observed after only 11 days of exercise, as suggested by some research [49,52,53], this measure would be a very useful tool in larger prevention studies. Use of biomarkers may help sort out the possible moderating and mediating effects of physical activity on prostate cancer.…”

“…In prostate cancer, insulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-1 (IGFBP-1), sex hormone-binding globulin (SHBG), expression of p53, and growth of prostate cancer cells in vitro have been suggested as possible markers of change in diet and/or exercise [50][51][52][53][54][55][56][57]. Each of these markers probes the signaling pathway at different junctures.…”