The effects of exercise on serum level myokines in prostate cancer patients and suppression of prostate cancer cells induced by alteration of systemic milieu

Over the past two decades, numerous clinical trials utilising exercise have emphasised its effectiveness in ameliorating cancer-related adverse effects. In addition, epidemiological studies have provided evidence for an inverse association between physical activity levels and prostate cancer (PCa) progression, further supporting the important role of exercise in the management of PCa. However, the mechanisms by which exercise reduces PCa growth and progression are not fully understood. While numerous hypotheses exist, exercise-induced circulatory milieu alterations have been proposed as a potential mechanism influencing tumour biology. However, previous studies are limited to the tumour suppressive role of the exercise-conditioned serum from non-PCa individuals. Furthermore, multiple preclinical studies have demonstrated reduced PCa cell growth by applying skeletal muscle secreting myokines. Androgen deprivation therapy (ADT), extensively used in the management of PCa, leads to compromised muscle physiology principally decreased mass and capacity to respond to exercise therapy, including myokine secretion. To date, no research has yet been undertaken to investigate systemic levels of myokines in patients with PCa on ADT. This research aimed to explore the serum levels of myokines after exercise in patients with PCa undergoing ADT, and the tumour suppressive role of exercise-conditioned serum from the patients. The latest evidence for the role of exercise-induced soluble and cell-free contents, especially myokines, is reviewed in Chapter Two. Three original studies (Chapters Three, Four, and Five) are reports on the effects of exercise on serum myokine levels and the tumour suppressive role of exercise-conditioned serum in patients with PCa undertaking ADT. In Chapters Three and Four, serum levels of myokines were measured before and after an exercise intervention in patients with localised disease and metastatic castrate-resistant prostate cancer (mCRPC), respectively, while on ADT. In addition, serum obtained from these patients was directly applied to the PCa cell line DU-145 with cell growth evaluated. In Chapter 5, serum myokine levels before and after a single exercise bout with subsequent evaluation of PCa cell growth was conducted in patients with mCRPC undertaking ADT. Finally, given the involvement of myokines in the interaction between skeletal muscle induced extracellular vesicles and PCa cells, Chapter Six presents a future research direction for the study on exercise-induced extracellular vesicles in PCa. Resting serum levels of myokines were significantly elevated after exercise training in PCa patients with localised and mCRPC on ADT, and the growth of the DU-145 PCa cell line was reduced in the presence of resting serum collected after exercise training compared to before (localised, baseline vs. post, 21.3%, P=0.012; mCRPC, control vs. exercise, 20.3%, P=0.029). Further, serum myokine levels were significantly elevated immediately after a single bout of exercise, and the PCa cell line growth was reduced (baseline vs. post, 16.9 %, P \u3c 0.01) with immediate post-exercise serum compared to baseline. This research provides evidence that exercise therapy alters soluble and cell-free contents in the circulatory milieu, especially myokines, supporting an anti-tumour environment. Further research investigating intercellular pathways of exercise-induced myokines in tumour suppression and the appropriate exercise mode and dosage for myokine adaptation and response in patients with PCa will enhance our understanding of exercise prescription for this patient group