Abstract
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.
Highlights
Physical inactivity, together with overwhelming calorie intake, is a main etiological factor that contributes to cancer development [1]
When SENCAR mice were treated with acetone vehicle, mouse double minute 2 homolog (MDM2) fluorescence intensity in exercised mice significantly decreased by 44% when compared with the sedentary control
Our previous studies conducted in a mouse skin cancer model demonstrated a down-regulation of insulin-like growth factor-1 (IGF-1) and IGF-1 signaling pathways was an essential cancer preventive target by exercise [9,10,11,12,13,14, 29]
Summary
Together with overwhelming calorie intake, is a main etiological factor that contributes to cancer development [1]. Large epidemiological studies and clinical trials have demonstrated that physical activity is effective in reducing the risk of various cancers, including breast, colon and colorectal, pancreatic, prostate, endometrial, ovarian, and lung cancer, with a reduction rate of 10–50% [2,3,4]. In addition to human studies, exercise intervention trials have been conducted in animal models to show a protective role against PTEN-deficient mouse liver tumors [6], DMH-induced rat colon cancer [7], and UVBinduced mouse skin carcinogenesis [8]. Our previous studies conducted in a mouse skin cancer model showed that treadmill exercise with iso-caloric intake of the sedentary counterpart could prevent cancer risk significantly [9,10]
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