Effects of Dietary Calorie Restriction or Exercise on the PI3K and Ras Signaling Pathways in the Skin of Mice

Abstract

Weight control by exercise and dietary calorie restriction (DCR) has been associated with reduced cancer risk, but the underlying mechanisms are not well understood. This study was designed to compare the effects of weight loss by increasing physical activity or decreasing calorie intake on tumor promoter-induced Ras-MAPK and PI3K-Akt pathways. SENCAR mice were randomly assigned to one of the following five groups: ad libitum-fed sedentary control, ad libitum-fed exercise (AL؉Exe), exercise but pair-fed at the amount as controls (PF؉Exe), 20% DCR, and 20% DCR plus exercise (DCR؉Exe). After 10 weeks, body weight and body fat significantly decreased in the groups of DCR, DCR؉Exe, and PF؉Exe when compared with the controls. AL؉Exe did not induce weight loss due to, at least in part, increased food intake. Plasma IGF-1 levels reduced significantly in DCR and DCR؉Exe but not PF؉Exe. The protein H-Ras and activated Ras-GTP significantly decreased in TPA-induced skin tissues of DCR-fed mice but not exercised mice. PI3K protein, phosphoserine Akt, and p42/p44-MAPK were reduced, however, in both DCR and PF؉Exe groups. Immunohistochemistry demonstrated that the significantly reduced H-Ras occurred in subcutaneous fat cells, while the reduced PI3K and PCNA took place only in the epidermis. Plasma leptin decreased in PF؉Exe, DCR, and DCR؉Exe, while the caspase-3 activity increased in DCR؉Exe only. Genomic microarray analysis further indicated that the expression of 34 genes relevant to PI3K and 31 genes to the MAPK pathway were significantly regulated by either DCR or PF؉Exe treatments. The reduced PI3K in PF؉Exe mice was partially reversed by IGF-1 treatment. The overall results of this study demonstrated that DCR abrogated both Ras and PI3K signaling, which might inhibit TPA-induced proliferation and anti-apoptosis. Selective inhibition of PI3K by PF؉Exe but not AL؉Exe seems more attributable to the magnitude of the caloric deficit and/or body fat loss than diet versus exercise comparison.The National Health and Nutrition Examination Survey indicates growing rates of obesity in American adults and overweight children over the past 20 years (1). Numerous prospective and case-control studies associated with weight control and physical activity estimate that excess body weight and sedentary life style account for about 39% endometrial, 25% kidney, 11% colon, 9% postmenopausal breast cancer, and 5% total cancer incidence (2-3). It has been suggested that those 25% over normal weight have a 33% greater cancer risk than those who maintain ideal body weight (4). Therefore, for many individuals, it would be advisable to maintain weight within the normal range to reduce their risk of cancer.Overweight/obesity is recognized as a reflection of a positive energy state that results from either over-consumption of energy or low energy expenditure. There is ample evidence that weight control via decreasing calorie intake and/or increasing physical activity reduces cancer risk in animal models. For almost a century, dietary calorie restr...

IGF-1 Mediates Exercise-Induced Phospholipid Alteration in the Murine Skin Tissues

“…Phospholipid profiling changes including PIs can be monitored by "lipidomics" via electrospray ionization tandem mass spectrometry (ESI/MS-MS) [22,23] By using lipidomics, we previously detected the phospholipid profile of mouse skin tissues and found that exercise with pair-feeding significantly modified some phospholipid species, including a 36% to 75% decrease of certain PI species along with a significant reduction of PI3K [24]. Taken together, our previous observational studies and other studies indicated that exercise with an iso-caloric diet significantly reduces body weight and skin carcinogenesis in correspondence with a low level of plasma IGF-1 and IGF-1-dependent PI3K signaling [7,24].…”

“…Research by the Hursting group suggested that it was negative energy balance rather than exercise alone that inhibited the development of intestinal polyps in APC Min mice [6]. Our previous study found that exercise with an iso-caloric intake, but not exercise with ad libitum feeding, was effective in controlling body weight gain and selectively abrogating the tumor promoter TPA-induced PI3K-Akt pathway in the skin epidermis, resulting in enhanced apoptosis and reduced proliferation [7].…”

“…IGF-1-dependent PI3K activity significantly contributed to the tumor promoting role of IGF-1 in the epidermis of BK5.IGF-1 mice [17]. Our previous studies have found that exercise with an iso-caloric diet decreased the plasma levels of IGF 1 with a corresponding down-expression of PI3K, phosphoserine Akt, and p42/p44-MAPK [7]. These results suggested that IGF-1 reduction and inactive PI3K pathway might play an important role in cancer prevention by exercise-induced weight control.…”

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…PI3K, which is frequently found mutated in human cancers (Yuan and Cantley, 2008), regulates growth and glucose metabolism in part via its downstream effector AKT (Vander Heiden et al, 2009). Notably, in normal cells, fasting can reduce PI3K signaling (Xie et al, 2007), leading to the protection of the cell. mTOR is another well-established master regulator, which integrates three major componentsgrowth factors, nutrients and cellular energy level (ATP)-to regulate cellular growth and metabolism.…”

Effects of Dietary Restriction on Cancer Development and Progression

“…According to previous studies (Xie et al 2007;Standard et al 2014), gene expression analysis of DEN-induced mice HCC cells revealed that DR restores functioning of many MAPK genes. MAPK pathway regulated by RAS promotes tumor growth and is one of the most important molecular targets for treatment of several types of cancers (Duan et al 2017).…”