Exercise shapes redox signaling in cancer

Abstract

In this paper of the special issue dedicated for the Olympics 2020, we put the light on an exciting facet of exercise-oncology, which may still be unknown to some audience. Accumulating convincing evidences show that exercise reduces cancer progression and recurrence mainly in colon and breast cancer patients. Interestingly, the positive effects of exercise on cancer outcomes were mainly observed when patients practiced vigorous exercise of 6 METs or more. At the molecular level, experimental studies highlighted that regular vigorous exercise could reduce tumor growth by driving changes in immune system, metabolism, hormones, systemic inflammation, angiogenesis and redox status. In the present review, we describe the main redox-sensitive mechanisms mediated by exercise. These redox mechanisms are of particular therapeutic interest as they may explain the emerging preclinical findings proving that the association of vigorous exercise with chemotherapy or radiotherapy improves the anti-cancer responses of both interventions. Clinical and preclinical studies converge to support the practice of exercise as an adjuvant therapy that improves cancer outcomes. The understanding of the underpinning molecular mechanisms of exercise in cancer can open new avenues to improve cancer care in patients.

Keywords: Cancer; Exercise; Redox signaling; Skeletal muscle.

Fig. 1

The benefits of vigorous exercise. Vigorous exercise of more than 6 MET improves cardiorespiratory fitness and muscle strength. Vigorous exercise reduces the risk of cancer progression and the evolution into lethal metastasis.

Fig. 2

A hypothetical scheme illustrating the differential impact of vigorous exercise on intra-tumor redox signature. Exercise alone is expected to produce an antioxidant response within tumor resulting in an anti-proliferative effect. While, the combination of exercise with radio/chemotherapy induces rather a pro-oxidant response promoting tumor cell death. More details about the mechanisms behind both responses are given in paragraph 4.

Fig. 3

Intra-muscular and intra-tumoral redox-sensitive mechanisms driven by exercise. Firstly, in exercised skeletal muscle cells, hormones like epinephrine and/or RONS activate a series of pathways such as, AMPK and cAMP/PKA/CREB, leading to the nuclear translocation of transcriptional factors like NF-κB and PGC-1α and transcription of genes encoding antioxidant enzymes and myokines. Secondly, skeletal muscle myokines are released into the bloodstream where they can reach tumor cells. We suppose that myokines will bind specific receptors on tumor cells and inhibit RONS-mediated activation of signaling pathways including MKK/JNK and MEK/p38 (basal levels of RONS are high in tumor cells given their accelerated metabolism), which results in less nuclear translocation of AP-1 and NF-κB transcriptional factors and less transcription of cyclin genes involved in cell proliferation. Some data indicate that myokines could also drive apoptosis of tumor cells but the mechanisms are still poorly elucidated.