P90 ribosomal S6 kinases: A bona fide target for novel targeted anticancer therapies?

The 90 kDa ribosomal S6 kinase (RSK) family of proteins is a group of highly conserved Ser/Thr kinases. They are downstream effectors of the Ras/ERK/MAPK signaling cascade. ERK1/2 activation directly results in the phosphorylation of RSKs, which further, through interaction with a variety of different downstream substrates, activate various signaling events. In this context, they have been shown to mediate diverse cellular processes like cell survival, growth, proliferation, EMT, invasion, and metastasis. Interestingly, increased expression of RSKs has also been demonstrated in various cancers, such as breast, prostate, and lung cancer. This review aims to present the most recent advances in the field of RSK signaling that have occurred, such as biological insights, function, and mechanisms associated with carcinogenesis. We additionally present and discuss the recent advances but also the limitations in the development of pharmacological inhibitors of RSKs, in the context of the use of these kinases as putative, more efficient targets for novel anticancer therapeutic approaches.

Effects of Irisin and Exercise on Metabolic Parameters and Reproductive Hormone Levels in High-Fat Diet-Induced Obese Female Mice.

It has been documented that exogenously administered irisin (1010 fibronectin-type III domain-containing 5 [FNDC5]), which is a new polypeptide hormone, induces the browning of subcutaneous fat and thermogenesis. In this study, effects of physical activity and exogenous administration of irisin were investigated on parameters related with reproduction and metabolism in the high-fat diet-induced obesity model of the female C57BL/6J mice. Sixty mice were gathered at age approximately 5 to 6weeks and were divided into 3 groups. Control group remained sedentary. Irisin group remained also sedentary but intravenously received 1010 FNDC5-expressing adenovirus after 20 weeks. Exercise group performed treadmill after 6 weeks. All mice were sacrificed 22 to 23 weeks after the start of the study. There was a significantly greater Δ weight in the controls compared with the irisin and exercise groups ( P < .05). Glucose and insulin levels were significantly higher in the controls ( P < .05). The serum irisin level was significantly higher in the exercise group ( P < .05). Serum luteinizing hormone levels were significantly increased in the irisin group ( P < .05). Serum anti-Müllerian hormone levels were significantly higher in irisin and exercise groups ( P < .05). There were significant negative correlations between serum irisin levels and Δ weight and homeostatic model assessment of insulin resistance ( r = -0.327, r = -0.297, respectively; P < .05 for both). The numbers of primordial follicles per ovary were similar ( P > .05), whereas primary and secondary follicles per ovary were higher in the irisin and exercise groups compared with controls ( P < .05). Pharmacologic introduction of irisin may improve metabolic factors such as insulin sensitivity and obesity by promoting weight loss and consequently improving the reproductive potential.