Exercise has been previously reported to lower cancer risk through reducing circulating IGF-1 and IGF-1-dependent signaling in a mouse skin cancer model. This study aims to investigate the underlying mechanisms by which exercise may down-regulate the IGF-1 pathway via p53 and p53-related regulators in the skin epidermis. Female SENCAR mice were pair-fed an AIN-93 diet with or without 10-week treadmill exercise at 20 m/min, 60 min/day and 5 days/week. Animals were topically treated with TPA 2 hours before sacrifice and the target proteins in the epidermis were analyzed by both immunohistochemistry and Western blot. Under TPA or vehicle treatment, MDM2 expression was significantly reduced in exercised mice when compared with sedentary control. Meanwhile, p53 was significantly elevated. In addition, p53-transcriptioned proteins, i.e., p21, IGFBP-3, and PTEN, increased in response to exercise. There was a synergy effect between exercise and TPA on the decreased MDM2 and increased p53, but not p53-transcripted proteins. Taken together, exercise appeared to activate p53, resulting in enhanced expression of p21, IGFBP-3, and PTEN that might induce a negative regulation of IGF-1 pathway and thus contribute to the observed cancer prevention by exercise in this skin cancer model.

Exercise has been previously reported to lower cancer risk through reducing circulating IGF-1 and IGF-1-dependent signaling in mouse skin cancer models. This study is to investigate the underlying mechanisms by which exercise might impact IGF-1 pathway regulated by p53 and p53-related proteins in mouse skin epidermis. Female SENCAR mice were pair fed an AIN-93 diet with or without 10-week treadmill exercise at 20 m/min for 60 min daily. Animals were topically treated with TPA or vehicle control 2 hours before sacrifice and the target proteins in the epidermis were assessed by immunohistochemistry and Western blotting. Under TPA or vehicle treatment, MDM2 was significantly reduced in exercised mice compared with sedentary control. Meanwhile, p53 was significantly increased. In addition, p53 transcription target proteins p21, IGFBP-3, and PTEN were elevated in response to exercise. An interaction between exercise and TPA was observed on the decrease of MDM2 and increase of p53, but not p53 down-regulated proteins. Taken together, exercise appears to activate p53 by reducing MDM2 suppression, resulting in enhanced expression of p21, IGFBP-3 and PTEN that might further induce a negative regulation of IGF-1 pathway and therefore contribute to the observed cancer prevention by exercise in this mouse skin cancer model.

The American Cancer Society estimates over 1 million new cancer cases to be diagnosed in 2013. Thus, efforts to understand the mechanisms of cancer prevention are vital. Physical activity is a modifiable lifestyle choice with the potential to reduce the risk of certain cancers. As such, research into the molecular mechanisms of how physical activity results in cancer prevention is imperative. Changes to the insulin‐like growth factor‐1(IGF‐1) pathway are important to cancer preventative mechanisms. Recently, the p53 protein was linked to IGF‐1 pathways under specific dietary conditions. Currently, there is a gap in knowledge surrounding p53 and the molecular mechanism of its involvement in IGF‐1 signaling pathways following exercise. The objective of this study was to first investigate the molecular mechanisms regulating exercise‐induced activation of p53. Female mice underwent a moderate exercise regime five days a week for ten weeks. Dorsal skin tissue was collected and prepared for down‐stream analysis. Using western blotting and immunohistochemistry techniques, we observed a significant increase in p53 nuclear protein in exercised mice which may result from changes with its interaction with MDM2. Planned experiments, including immunoprecipitations, aim to investigate the interaction between p53 and its regulatory proteins. Furthermore, future experiments will focus on p53 and its effects on the IGF‐1 signaling pathway following exercise. Completion of these experiments will provide new information regarding p53‐related pathways in the cancer preventative effects of exercise. Grant Funding Source: Supported by: NIH CA167678