Myoglobin Inhibits Breast Cancer Cell Fatty Acid Oxidation and Migration via Heme-dependent Oxidant Production and Not Fatty Acid Binding.

The monomeric heme protein myoglobin (Mb), traditionally thought to be expressed exclusively in cardiac and skeletal muscle, is now known to be expressed in approximately 40% of breast tumors. While Mb expression is associated with better patient prognosis, the molecular mechanisms by which Mb limits cancer progression are unclear. In muscle, Mb's predominant function is oxygen storage and delivery, which is dependent on the protein's heme moiety. However, prior studies demonstrate that the low levels of Mb expressed in cancer cells preclude this function. Recent studies propose a novel fatty acid binding function for Mb via a lysine residue (K46) in the heme pocket. Given that cancer cells can upregulate fatty acid oxidation (FAO) to maintain energy production for cytoskeletal remodeling during cell migration, we tested whether Mb-mediated fatty acid binding modulates FAO to decrease breast cancer cell migration. We demonstrate that the stable expression of human Mb in MDA-MB-231 breast cancer cells decreases cell migration and FAO. Site-directed mutagenesis of Mb to disrupt Mb fatty acid binding did not reverse Mb-mediated attenuation of FAO or cell migration in these cells. In contrast, cells expressing Apo-Mb, in which heme incorporation was disrupted, showed a reversal of Mb-mediated attenuation of FAO and cell migration, suggesting that Mb attenuates FAO and migration via a heme-dependent mechanism rather than through fatty acid binding. To this end, we show that Mb's heme-dependent oxidant generation propagates dysregulated gene expression of migratory genes, and this is reversed by catalase treatment. Collectively, these data demonstrate that Mb decreases breast cancer cell migration, and this effect is due to heme-mediated oxidant production rather than fatty acid binding. The implication of these results will be discussed in the context of therapeutic strategies to modulate oxidant production and Mb in tumors. Highlights: Myoglobin (Mb) expression in MDA-MB-231 breast cancer cells slows migration.Mb expression decreases mitochondrial respiration and fatty acid oxidation.Mb-dependent fatty acid binding does not regulate cell migration or respiration.Mb-dependent oxidant generation decreases mitochondrial metabolism and migration.Mb-derived oxidants dysregulate migratory gene expression.

Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation.

In response to signals associated with infection or tissue damage, macrophages undergo a series of dynamic phenotypic changes. Here we show that during the response to LPS and interferon-γ stimulation, metabolic reprogramming in macrophages is also highly dynamic. Specifically, the TCA cycle undergoes a two-stage remodeling: the early stage is characterized by a transient accumulation of intermediates including succinate and itaconate, while the late stage is marked by the subsidence of these metabolites. The metabolic transition into the late stage is largely driven by the inhibition of pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which is controlled by the dynamic changes in lipoylation state of both PDHC and OGDC E2 subunits and phosphorylation of PDHC E1 subunit. This dynamic metabolic reprogramming results in a transient metabolic state that strongly favors HIF-1α stabilization during the early stage, which subsides by the late stage; consistently, HIF-1α levels follow this trend. This study elucidates a dynamic and mechanistic picture of metabolic reprogramming in LPS and interferon-γ stimulated macrophages, and provides insights into how changing metabolism can regulate the functional transitions in macrophages over a course of immune response.

Absolute photoluminescence quantum efficiency measurement of light-emitting thin films.

We developed an integrated monochromatic excitation light source integrating sphere based detection system to accurately characterize the absolute photoluminescence quantum efficiency of commonly used polymer light emitting films without using a reference sample. Our methodology is similar to the method reported by de Mello et al. [Adv. Mater. 9, 230 (1997)] In this Note, we show that the absolute photoluminescence quantum efficiency might only be measured when an appropriate calibration of the spectral variation of the measurement system is done. This calibration is especially important when employing a short excitation wavelength (<400 nm) for common silicon-based detector.

High dose zinc increases hospital admissions due to genitourinary complications.

PURPOSE: Zinc is a common dietary supplement that is widely believed to have beneficial health effects. To assess the impact of high dose supplemental zinc on genitourinary diseases we analyzed a recent randomized trial comparing zinc, antioxidants and their combination to placebo for complications related to the genitourinary tract. MATERIALS AND METHODS: In a further analysis of the recent Age-related Eye Disease Study we examined the data pool for primary International Classification of Diseases, 9th revision codes given for hospital admissions related to urological problems. The Age-Related Eye Disease Study randomized 3,640 patients with age related macular degeneration to 1 of 4 study arms, including placebo, antioxidants (500 mg vitamin C, 400 IU vitamin E and 15 mg beta-carotene), 80 mg zinc and antioxidant plus zinc. Statistical analyses using Fisher's exact test were performed. RESULTS: We found a significant increase in hospital admissions due to genitourinary causes in patients on zinc vs nonzinc formulations (11.1% vs 7.6%, p = 0.0003). The risk was greatest in male patients (RR 1.26, 95% CI 1.07-1.50, p = 0.008). In the study group of 343 patients requiring hospital admission the most common primary International Classification of Diseases, 9th revision codes included benign prostatic hyperplasia/urinary retention (benign prostatic hyperplasia), urinary tract infection, urinary lithiasis and renal failure. When comparing zinc to placebo, significant increases in urinary tract infections were found (p = 0.004), especially in females (2.3% vs 0.4%, RR 5.77, 95% CI 1.30-25.66, p = 0.013). Admissions for urinary lithiasis approached significance in men on zinc compared to placebo (2.0% vs 0.5%, RR = 4.08, 95% CI 0.87-19.10). There was no increase in prostate or other cancers with zinc supplementation. A significant decrease in prostate cancer diagnoses was seen in patients receiving antioxidants vs placebo (RR = 0.6, 95% CI 0.49-0.86, p = 0.049). Subgroup analysis revealed that this finding was significant in men who smoked but not in nonsmokers. CONCLUSIONS: Zinc supplementation at high levels results in increased hospitalizations for urinary complications compared to placebo. These data support the hypothesis that high dose zinc supplementation has a negative effect on select aspects of urinary physiology.