Exercise Activates p53 and Negatively Regulates IGF-1 Pathway in Epidermis within a Skin Cancer Model

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.

TRIM59 overexpression correlates with poor prognosis and contributes to breast cancer progression through AKT signaling pathway

“…p53 plays a vital role in the regulation if cell cycle transition, checkpoint activation, and apoptotic machinery in tumor cells, which control expression of p21 and p27 . It has been reported that TRIM59, as an E3 ubiquitin ligases, was able to interacted with p53, increasing its ubiquitination and degradation in gastric cancer cells .…”

“…Our results showed that TRIM59 induced paclitaxel resistance with apoptosis inhibition. To find out the underlying mechanism, we examined several related protein and found that TRIM59 downregulated cleaved caspase 3, cleaved caspase 9, cleaved PARP, and cytochrome c release, indicating TRIM59 could reduce the activation p53 plays a vital role in the regulation if cell cycle transition, checkpoint activation, and apoptotic machinery in tumor cells, [21][22][23][24] which control expression of p21 and p27. [25][26][27] It has been reported that TRIM59, as an E3 ubiquitin ligases, was able to interacted with p53, increasing its ubiquitination and degradation in gastric cancer cells.…”

Exercise and cancer: a position statement from the Spanish Society of Medical Oncology

“…Exercise can have an impact on tumor development, growth or dissemination through several mechanisms. First, exercise might help to prevent cancer by reducing the circulating levels of several mediators, such as insulin growth factor-1 (IGF-1) [9][10][11][12][13][14], a mitogen that triggers cell proliferation [15]. Exercise can also reduce the levels of hyperphosphorylated retinoblastoma protein (Rb) in a chemically induced rat model of mammary carcinogenesis [16,17], increase ß-catenin phosphorylation in colon polyps [18,19], and reduce the levels of micro-RNA 21 [20].…”

“…Exercise can upregulate tumor suppressors, such as the tumor suppressor programmed cell death protein 4 in a murine model of estrogen receptor-positive breast cancer (BC) [21]. In addition, exercise-induced catecholamines might reduce BC development through activation of the Hippo tumor suppressor pathway [22] and exercise-induced increased p53 activation, leading to tumor prevention, as shown in mouse models of skin [13,23] and lung [24] cancer.…”

Impact of cancer rehabilitation on the prognosis of patients with hepatocellular carcinoma

“…Exercise improves insulin resistance and decreases levels of insulin-like growth factor 1 in patients with breast cancer (39). Moreover, exercise is also known to enhance the expression of p21, insulin-like growth factor-binding protein-3, and PTEN, which suppress insulin-like growth factor 1 signaling in a cancer mouse model (41).…”