Nuclear Receptors and the Warburg effect in cancer

In 1927 Otto Warburg established that tumours derive energy primarily from the conversion of glucose to lactic acid and only partially through cellular respiration involving oxygen. In the 1950’s he proposed that all causes of cancer reflected different mechanisms of disabling cellular respiration in favour of fermentation (now termed aerobic glycolysis). The role of aberrant glucose metabolism in cancer is now firmly established. The shift away from oxidative phosphorylation towards the metabolically expensive aerobic glycolysis is somewhat counter-intuitive given its wasteful nature. Multiple control processes are in place to maintain cellular efficiency and it is likely that these mechanisms are disrupted to facilitate the shift to the reliance on aerobic glycolysis. One such process of cell control is mediated by the nuclear receptor superfamily. This large family of transcription factors plays a significant role in sensing environmental cues and controlling decisions on proliferation, differentiation and cell death for example, to regulate glucose uptake and metabolism and to modulate the actions of oncogenes and tumour suppressors. In this review we highlight mechanisms by which nuclear receptors actions are altered during tumorigenic transformation and can serve to enhance the shift to aerobic glycolysis. At the simplest level, a basic alteration in NR behaviour can serve to enhance glycolytic flux thus providing a basis for enhanced survival within the tumour micro-environment. Ameliorating the enhanced NR activity in this context may help to sensitize cancer cells to Warburg targeted therapies and may provide future drug targets

Purification and characterization of native human insulin-like growth factor binding protein-6

Insulin-like growth factor binding proteins (IGFBPs) are key regulators of insulin-like growth factor (IGF) mediated signal transduction and thereby can profoundly influence cellular phenotypes and cell fate. Whereas IGFBPs are extracellular proteins, intracellular activities were described for several IGFBP family members, such as IGFBP-3, which can be reinternalized by endocytosis and reaches the nucleus through routes that remain to be fully established. Within the family of IGFBPs, IGFBP-6 is unique for its specific binding to IGF-II. IGFBP-6 was described to possess additional IGF-independent activities, which have in part been attributed to its translocation to the nucleus; however, cellular uptake of IGFBP-6 was not described. To further explore IGFBP-6 functions, we developed a new method for the purification of native human IGFBP-6 from cell culture supernatants, involving a four-step affinity purification procedure, which yields highly enriched IGFBP-6. Whereas protein purified in this way retained the capacity to interact with IGF-II and modulate IGF-dependent signal transduction, our data suggest that, unlike IGFBP-3, human IGFBP-6 is not readily internalized by human tumor cells. To summarize, this work describes a novel and efficient method for the purification of native human insulin-like growth factor binding protein 6 (IGFBP-6) from human cell culture supernatants, applying a four-step chromatography procedure. Intactness of purified IGFBP-6 was confirmed by IGF ligand Western blot and ability to modulate IGF-dependent signal transduction. Cellular uptake studies were performed to further characterize the purified protein, showing no short-term uptake of IGFBP-6, in contrast to IGFBP-3

Effect of creatine on body composition and strength gains after 4 weeks of resistance training in previously nonresistance-trained humans

This study examined the effects of Cr supplementation on muscle strength in conjunction with resistance training in nonresistance-trained males utilizing strategies previously reported in the literature to help optimize muscle Cr uptake. Nineteen nonresistance-trained males underwent 4 weeks of resistance training (3 days · week−1) while assigned to Cr (20 g · d−1 Cr + 140 g · d−1 glucose) for 7 days (loading), followed by 5 g · d−1 Cr + 35 g · d−1 glucose for 21 days (maintenance; n = 9) or placebo (160 g · d−1 glucose [loading] followed by 40 g · d−1 [maintenance; n = 10]). In subjects classified as “responders” to Cr on the basis of body mass changes (n = 7), the magnitude of change in 180∞ · s−1 isokinetic (p = .029) and isometric (p = .036) force was greater compared to the placebo group. A positive correlation was found between changes in body mass and 180º · s−1 isokinetic (loading: r = 0.68, p = .04; maintenance: r = 0.70, p = .037) and isometric (loading: r = 0.82, p &lt; .01) force. Estimated Cr uptake was also positively correlated with changes in 60º · s−1 (r = 0.90, p &lt; .01) and 180º · s−1 (r = 0.68, p = .043) isokinetic force, and isometric force (r = 0.71, p = .033). These results indicate that Cr supplementation can increase muscle strength (allied with 4 weeks of strength training) but only in subjects whose estimated Cr uptake and body mass are significantly increased; the greater the Cr uptake and associated body mass changes, the greater the performance gains.</jats:p