The main results of this study were: 1) the incubation of PC3 prostate cancer cell line with plasma acquired from young men with high PF and with post-exercise training plasma of elderly individuals leads to lower cell viability and proliferation rates after 48 h of treatment; 2) conditioned post-training plasma-induced mitochondrial membrane depolarization and higher mitochondrial ROS, but not cytosolic ROS, in PC3 prostate cancer cells without changes in apoptosis/necrosis rate; 3) 8 weeks of multimodal exercise training increases the systemic levels of IL-2, IFN-α, and FGF-1 and decreases the TNF-α concentrations in aged individuals. Taken together, we showed for the first time that multimodal exercise training induces systemic inflammatory adaptations in institutionalized elderly individuals in parallel to the enhanced anticarcinogenic potential of blood mediators against prostate cancer through changes in mitochondrial membrane polarization and mitochondrial ROS generation.
Here, the plasma collected from highly conditioned men, but not from low PF individuals, decreased the PC3 cell viability and lowered cell proliferation. These results are in line with the previously reported by a series of systematic reviews and meta-analysis recently published who demonstrated the anticarcinogenic potential of peripheral blood factors of exercised individuals (6, 7, 16). Interestingly, the incubation of conditioned plasma obtained from institutionalized elderly engaged in multimodal exercise training decreased both cell viability and proliferation in PC3 prostate cancer cell line. It was hypothesized that exercise-induced biochemical mediators release, mainly myokines and immunomodulatory cytokines, have a critical role in decreasing cancer cell viability and growth (5). Interestingly, apoptosis and necrosis rate were unchanged after the incubation of PC3 prostate cell line with conditioned exercised-plasma, confirming previously data who demonstrate that exercised mediators reduce cell viability without changes in cell death pathways (17, 18). Notably, several studies were conducted using acute exercise session models and the tumor-suppressive effects of chronic longitudinal exercise training is poorly studied.
Here, we describe for the first time the mitochondrial dysfunction in PC3 prostate cell line incubated with post-exercise training plasma of elderly. Targeting cancer cell mitochondria has been long suggested as a therapeutic approach to control cell proliferation and growth. In this sense, several pharmacological therapies alter mitochondria function to induce cell death and lower tumor progression (17). In the present study we show that depolarization of the mitochondrial membrane potential associated with increasing superoxide production (mitochondrial ROS) after 12h of PC3 incubation with conditioned plasma of elderly. Furthermore, mitochondria membrane depolarization leads to translocation of apoptosis-induced factor (AIF) to the nuclei and activation of caspase-12 associated with endoplasmic reticulum to induce cell death(18). Moreover, mitochondrial membrane depolarization directly affects complex II and its function in electric chain transport, leading to ROS generation and the activation of apoptotic cascade(19). However, the lack of changes in apoptosis rate after conditioned plasma incubation may indicate the need of repeated or prolonged incubation time to induce cancer cell death.
Here, exercise training was able to decrease proinflammatory TNF-α levels, suggesting a role to induce anti-inflammatory profile in institutionalized elderlies. However, other classic proinflammatory mediators, such as IL-6, IL-17a and IL-1β, did not change after 8 weeks of multimodal exercise. These results may suggest that the potential anti-inflammatory adaptations observed in previous observational and longitudinal studies (20) may need a longer intervention time than 8 weeks to be achieved. On the other hand, we are the first study to observe increased FGF-1 increased after exercise training period. FGF-1, also called acidic FGF, plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and migration (21). Interestingly, experimental studies shows that mice treated with FGF-1 restore blood glucose levels and endothelial function, highlighting the role of this growth factor in the vascular health and metabolic control(22). Furthermore, mutated fgf1 gene is linked to accelerated neurological senescence profile in mice(23). Thus, FGF-1 emerges as an important biological mediator to the control of aging through exercise training.
We found an increases in IL-2 and IFN-α levels in the peripheral blood of elderly after exercise training period. Both IL-2 and IFN-α have strong anti-tumorigenic directly effects against cancer cell, and in vitro cytokine treatment of prostate tumor cell lines can effectively alter a number of prostate carcinoma properties closely associated with tumor invasion and metastatic phenotype(24). In addition, the correlation between post-training cytokine levels and PC3 cell viability, proliferation and mitochondrial function revealed some associations between changes in systemic inflammatory mediators and cancer cell phenotype.
In conclusion, this longitudinal study described for the first time the potential of conditioned plasma to decrease cell viability and proliferation in PC3 prostate tumor cell line. We also demonstrated a new mechanistic pathway by which exercise may alters prostate cell function through mitochondrial function, mainly by mitochondrial membrane depolarization and superoxide formation. These changes were accompanied by alterations in several systemic inflammatory mediators after multimodal exercise training. Collectively, changes in blood factors composition by exercise training contribute to the control of prostate tumorigenesis, suggesting the role of exercise as an adjuvant therapeutic in cancer treatment and prevention.