Heme, an Essential Nutrient from Dietary Proteins, Critically Impacts Diverse Physiological and Pathological Processes

Heme constitutes 95% of functional iron in the human body, as well as two-thirds of the average person’s iron intake in developed countries. Hence, a wide range of epidemiological studies have focused on examining the association of dietary heme intake, mainly from red meat, with the risks of common diseases. High heme intake is associated with increased risk of several cancers, including colorectal cancer, pancreatic cancer and lung cancer. Likewise, the evidence for increased risks of type-2 diabetes and coronary heart disease associated with high heme intake is compelling. Furthermore, recent comparative metabolic and molecular studies of lung cancer cells showed that cancer cells require increased intracellular heme biosynthesis and uptake to meet the increased demand for oxygen-utilizing hemoproteins. Increased levels of hemoproteins in turn lead to intensified oxygen consumption and cellular energy generation, thereby fueling cancer cell progression. Together, both epidemiological and molecular studies support the idea that heme positively impacts cancer progression. However, it is also worth noting that heme deficiency can cause serious diseases in humans, such as anemia, porphyrias, and Alzheimer’s disease. This review attempts to summarize the latest literature in understanding the role of dietary heme intake and heme function in diverse diseases

The nuclear localization of SWI/SNF proteins is subjected to oxygen regulation

Abstract Background Hypoxia is associated with many disease conditions in humans, such as cancer, stroke and traumatic injuries. Hypoxia elicits broad molecular and cellular changes in diverse eukaryotes. Our recent studies suggest that one likely mechanism mediating such broad changes is through changes in the cellular localization of important regulatory proteins. Particularly, we have found that over 120 nuclear proteins with important functions ranging from transcriptional regulation to RNA processing exhibit altered cellular locations under hypoxia. In this report, we describe further experiments to identify and evaluate the role of nuclear protein relocalization in mediating hypoxia responses in yeast. Results To identify regulatory proteins that play a causal role in mediating hypoxia responses, we characterized the time courses of relocalization of hypoxia-altered nuclear proteins in response to hypoxia and reoxygenation. We found that 17 nuclear proteins relocalized in a significantly shorter time period in response to both hypoxia and reoxygenation. Particularly, several components of the SWI/SNF complex were fast responders, and analysis of gene expression data show that many targets of the SWI/SNF proteins are oxygen regulated. Furthermore, confocal fluorescent live cell imaging showed that over 95% of hypoxia-altered SWI/SNF proteins accumulated in the cytosol in hypoxic cells, while over 95% of the proteins were nuclear in normoxic cells, as expected. Conclusions SWI/SNF proteins relocalize in response to hypoxia and reoxygenation in a quick manner, and their relocalization likely accounts for, in part or in whole, oxygen regulation of many SWI/SNF target genes.</p

Comparative proteomic analysis reveals characteristic molecular changes accompanying the transformation of nonmalignant to cancer lung cells

To identify changes in proteins accompanying transformation of normal lung epithelial cells to cancer cells, we performed a comparative proteomic study using two cell lines representing matching normal and cancer cells. Strikingly, a good number of detected actin cytoskeletal proteins were preferentially downregulated in cancer cells, while similar numbers of proteins in other organelles were up or downregulated. We also found that the formation of stress fibers and focal adhesions were substantially decreased in cancer cells. Protein network analysis showed that the altered proteins are highly connected. These results provide novel insights into the molecular mechanism promoting lung cancer progression

The Swi3 protein plays a unique role in regulating respiration in eukaryotes

Synopsis Recent experimental evidence increasingly shows that the dysregulation of cellular bioenergetics is associated with a wide array of common human diseases, including cancer, neurological diseases and diabetes. Respiration provides a vital source of cellular energy for most eukaryotic cells, particularly high energy demanding cells. However, the understanding of how respiration is globally regulated is very limited. Interestingly, recent evidence suggests that Swi3 is an important regulator of respiration genes in yeast. In this report, we performed an array of biochemical and genetic experiments and computational analysis to directly evaluate the function of Swi3 and its human homologues in regulating respiration. First, we showed, by computational analysis and measurements of oxygen consumption and promoter activities, that Swi3, not Swi2, regulates genes encoding functions involved in respiration and oxygen consumption. Biochemical analysis showed that the levels of mitochondrial respiratory chain complexes were substantially increased in Δswi3 cells, compared with the parent cells. Additionally, our data showed that Swi3 strongly affects haem/oxygen-dependent activation of respiration gene promoters whereas Swi2 affects only the basal, haem-independent activities of these promoters. We found that increased expression of aerobic expression genes is correlated with increased oxygen consumption and growth rates in Δswi3 cells in air. Furthermore, using computational analysis and RNAi knockdown, we showed that the mammalian Swi3 BAF155 and BAF170 regulate respiration in HeLa cells. Together, these experimental and computational data demonstrated that Swi3 and its mammalian homologues are key regulators in regulating respiration

The levels of heme biosynthesis and heme biosynthetic enzymes are enhanced in lung cancer cells.

<p>The normal HBEC30KT lung epithelial (HBEC) and NSCLC HCC4017 (HCC) cells were cultured, RNA and proteins were extracted. Transcript levels were detected by using quantitative real-time RT-PCR, and protein levels were detected by using Western blotting. (A) The levels of heme biosynthesis in normal and NSCLC cells. (B) The transcript level of heme biosynthetic enzyme ALAS1 in normal and NSCLC cells. (C) The transcript level of heme biosynthetic enzyme ALAS2 in normal and NSCLC cells. (D) The protein level of heme biosynthetic enzyme ALAS1 in normal and NSCLC cells. The protein level of β-actin in the samples was used for normalization. For statistical analysis, the levels in cancer cells were compared to the levels in normal cells, by using Welch 2-sample t-test. *, p value <0.05; **, p value <0.005.</p

Cancer Cells Substantially Increase the Rates of Glucose and Oxygen Consumption^*.

*<p>The rates of glucose uptake and oxygen consumption are shown in nmol/min/10⁶ cells, while the mitochondrial DNA level (mtDNA) is shown as the ratio of threshold cycle number of mitochondrial DNA vs. nuclear DNA, measured by real-time PCR.</p

Cartoon illustrating key bioenergetics changes in NSCLC cells.

<p>Cancer cells exhibit enhanced expression levels of the rate-limiting heme biosynthetic enzyme, 5-aminolevulinic acid synthase (ALAS) and the heme uptake proteins HCP1 and HRG1. As such, heme availability in cancer cells is substantially increased, leading to increased production and levels of various oxygen-utilizing hemoproteins, such as cytochrome c, cytoglobin, Cox-2 and cytochrome P450. The increase in these hemoproteins ultimately leads to intensified oxygen consumption and the generation of cellular energy by respiration. This in turn causes increased cellular energy production, cell proliferation, migration and colony formation.</p