Exercise training as a modulator of epigenetic events in prostate tumors.

BACKGROUND: Exercise is increasingly recognized as an effective strategy to improve cancer prevention and prognosis. Several biological mechanisms mediating these benefits have been proposed, but the role of epigenetics remains largely unknown. Since epigenetics is highly susceptible to lifestyle factors, we hypothesized that exercise could affect the epigenome landscape in cancer tissues. METHODS: Rats implanted with AT1 prostate tumors were randomized to either control or exercise training. microRNA expression, DNA methylation and histone acetylation were analyzed in the tumor tissue. RESULTS: MiR-27a-5p appeared to be differently expressed between sedentary and trained rats. Furthermore, exercise increased global DNA methylation and decreased DNA methyltransferases mRNA expression in the tumor tissue. Histone acetylation however remained unaltered. CONCLUSION: Overall, exercise might reverse some of the cancer-related epigenetic alterations in the prostate tumor tissue.

Exercise training improves radiotherapy efficiency in a murine model of prostate cancer.

Engaging in exercise while undergoing radiotherapy (RT) has been reported to be safe and achievable. The impact of exercise training (ET) on RT efficiency is however largely unknown. Our study aims to investigate the interactions between ET and RT on prostate cancer growth. Athymic mice received a subcutaneous injection of PPC-1 cells and were randomly assigned to either cancer control, cancer ET, cancer RT, or cancer RT combined with ET (CaRT-ET). Mice were sacrificed 24 days post-injection. All three intervention groups had reduced tumor size, the most important decrease being observed in CaRT-ET mice. Apoptotic marker cleaved caspase-3 was not modified by ET, but enhanced with RT. Importantly, this increase was the highest when the two strategies were combined. Furthermore, NK1.1 staining and gene expression of natural killer (NK) cell receptors Klrk1 and Il2rß were not affected by ET alone but were increased with RT, this effect being potentiated when combined with ET. Overall, our study shows that (a) ET enhances RT efficiency by potentiating NK cell infiltration, and (b) while ET alone and ET combined with RT both reduce tumor growth, the mechanisms mediating these effects are different.

Exercise training combined with antioxidant supplementation prevents the antiproliferative activity of their single treatment in prostate cancer through inhibition of redox adaptation.

In preclinical models, exercise training (ET) or pomegranate juice (PJ) prevents prostate cancer progression. Here, we hypothesized that physical exercise combined with antioxidants could induce synergistic effects through oxidative stress modulation. Forty male Copenhagen rats with prostate tumors were divided into four groups: control, PJ, ET, and PJ+ET. Rats from the PJ group consumed 750 µl of PJ daily, rats from the ET group ran on a treadmill 5 days per week, and PJ+ET rats received the combined treatment. Each week, tumor growth was evaluated. After 4 weeks of treatment, the rats were euthanized and blood, muscles, and tumors were collected. Tumor Ki67, extracellular signal-regulated kinase (ERK) activation, Bcl-2 expression, and enzymatic and nonenzymatic antioxidant defenses, as well as oxidative stress markers (oxidized base, lipid peroxidation, protein carbonylation), were measured. PJ or ET significantly decreased prostate tumor proliferation (Ki67 staining, p<0.05) through the modulation of ERK phosphorylation, whereas the combination of treatments did not limit cancer progression. PJ significantly reduced Bcl-2 expression in tumors (p<0.05) and the combination of PJ and ET prevented this effect. PJ or ET increased enzymatic antioxidant defenses in muscle, PJ increased nonenzymatic antioxidant defenses in plasma and whole blood. In addition, PJ reduced TBARS and 8-oxodGuo levels in tumors as well as ET (p<0.05), whereas protein carbonyl levels were not affected by these two strategies. Paradoxically, association of PJ+ET did not increase antioxidant defenses and no reduction in oxidative stress markers was induced. Loading cancer cells with antioxidants blunts the positive effects of ET and interferes with important reactive oxygen species-mediated physiological processes such as antioxidant adaptations.

Antioxidants and muscle atrophy in colon cancer: beneficial or deleterious effects?

Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of body weight, mainly due to adipose tissue and skeletal muscle wasting. Muscle atrophy leads to a progressive functional impairment and contributes to a negative impact on patient's quality of life. Oxidative Stress (OS) seems to play a major role in muscle atrophy since OS markers are increased in plasma and muscles of cancer patients. Thus, supplementing patients with antioxidant may reduce OS and restore muscle mass and function. In this study, we assess the effects of antioxidant supplementation on muscle atrophy in a model of colon 26 tumor-bearing mice (C26-mice). Five-week old Balb/c mice receive a subcutaneous injection of PBS or C26 cancer cells with or without daily supplementation with Allopurinol or Oxynov (50mg/kg and 163mg/kg respectively). Blood and muscles are removed 20-22 days after injection. C26-mice develop cachexia, with a decrease in total body weight, muscular endurance and muscle fibers diameter. Furthermore, injection of C26 induces ubiquitination of muscles proteins, suggesting the enhancement of muscle proteolysis. Contrary to our expectations, supplementation with antioxidants (Allopurinol or Oxynov) doesn't prevent weight loss and muscle atrophy but induces premature death of mice. C26-mice exhibit systemic oxidative stress markers (i.e. carbonyl proteins and 4-HNE) and show an increase in phosphorylation levels of the redox-dependent kinase, JNK, in the atrophied muscles (i.e. gastrocnemius). Surprisingly, Allopurinol or Oxynov decrease the total antioxidant defenses in plasma but has no effect on C26-induced oxidative damages and JNK phosphorylation. Our results are in agreement with recent reports showing deleterious effects of antioxidants supplementation in lung and prostate cancer. However, such findings require further investigations.

Prostate cancer and physical activity: adaptive response to oxidative stress.

Prostate cancer is the most common form of cancer affecting men in the Western world. Its relative incidence increases exponentially with age and a steady increase is observed with extended life span. A sedentary lifestyle represents an important risk factor and a decrease in prostate cancer prevalence is associated with exercise. However, the molecular mechanisms involved in this process remain unknown. We hypothesize that reactive oxygen species generated by physical exercise are a key regulatory factor in prostate cancer prevention. Aging is correlated with increased oxidative stress (OS), which in turn provides a favorable environment for tumorigenesis. Running training is known to enhance the antioxidant defense system, reducing oxidative stress. In this context, the decrease in OS induced by exercise may delay the development of prostate cancer. This review focuses on oxidative stress-based mechanisms leading to prostate cancer sensitization to exercise, which could have some impact on the development of novel cancer therapeutic strategies.