Transferrin and transferrin receptors update

Kawabata, Hiroshi

doi:10.1016/j.freeradbiomed.2018.06.037

Cited by 424 publications

(333 citation statements)

References 159 publications

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“…Heme synthesis in nonerythroid cells is generally not affected by iron (34). Nonetheless, we detected the levels of transferrin receptor (TFRC), which is responsible for cellular iron uptake from the circulation (35). We found that TFRC levels were increased in some, whereas unaffected or decreased in other NSCLC cell lines (Fig.…”

Section: Resultsmentioning

confidence: 90%

Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non–Small Cell Lung Cancer Cells

et al. 2019

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HSP2HSP2 HEME HCP1 HRG1 HEME HEME HEME CYT NUC ER ALA SLung cancer cells exhibit elevated heme synthesis and uptake, which promotes tumorigenic functions. Heme-sequestering peptide 2 (HSP2) inhibits heme uptake and suppresses tumor growth. V [ ] Lung tumors Non-small cell lung cancer cell Normal lung I II III IV ATP ADPTumors of human non-small cell lung cancer (NSCLC) are heterogeneous but exhibit elevated glycolysis and glucose oxidation relative to benign lung tissues. Heme is a central molecule for oxidative metabolism and ATP generation via mitochondrial oxidative phosphorylation (OXPHOS). Here, we showed that levels of heme synthesis and uptake, mitochondrial heme, oxygen-utilizing hemoproteins, oxygen consumption, ATP generation, and key mitochondrial biogenesis regulators were enhanced in NSCLC cells relative to nontumorigenic cells. Likewise, proteins and enzymes relating to heme and mitochondrial functions were upregulated in human NSCLC tissues relative to normal tissues. Engineered heme-sequestering peptides (HSP) reduced heme uptake, intracellular heme levels, and tumorigenic functions of NSCLC cells. Addition of heme largely reversed the effect of HSPs on tumorigenic functions. Furthermore, HSP2 significantly suppressed the growth of human NSCLC xenograft tumors in mice. HSP2-treated tumors exhibited reduced oxygen consumption rates (OCR) and ATP levels. To further verify the importance of heme in promoting tumorigenicity, we generated NSCLC cell lines with increased heme synthesis or uptake by overexpressing either the ratelimiting heme synthesis enzyme ALAS1 or uptake protein SLC48A1, respectively. These cells exhibited enhanced migration and invasion and accelerated tumor growth in mice. Notably, tumors formed by cells with increased heme synthesis or uptake also displayed elevated OCRs and ATP levels. These data show that elevated heme flux and function underlie enhanced OXPHOS and tumorigenicity of NSCLC cells. Targeting heme flux and function offers a potential strategy for developing therapies for lung cancer. IntroductionLung cancer is the leading cause of cancer-related deaths in the United States (1). About 85% of cases are non-small cell lung cancer (NSCLC). Although several chemotherapeutic and targeted therapeutic agents are approved for treating lung cancer, the 5-year survival rate remains 18%. The effectiveness of targeted therapies for lung cancer is lowered by the presence of multiple driver genes and intratumoral genetic heterogeneity (2). Likewise, three PD-1/PD-L1 checkpoint inhibitors, nivolumab, pembrolizumab, and atezolizumab, generally extend median overall survival by about 3 months for second-line treatment of advanced NSCLC, compared with docetaxel alone (3-5). In the front-line setting, the median progression-free survival extends from 6.0 months with platinum-doublet chemotherapy to 10.3 months with pembrolizumab in patients with untreated NSCLC characterized by a high level of PD-L1 expression (6). Thus, alternative therapeutic strategies are still needed for lung canc...

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Section: Resultsmentioning

confidence: 90%

Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non–Small Cell Lung Cancer Cells

et al. 2019

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“…Serotransferrin was identified as a major deimination candidate in the current study both in cow serum and serum-EVs. It is an iron-binding protein with multifaceted functions in development and immunity [144,145]. Serotransferrin is found both in plasma and mucosal tissue and has important roles in anti-pathogenic responses across phylogeny, including in cattle, by withdrawing iron from pathogens including bacteria, fungi and viruses [146][147][148][149].…”

Section: Discussionmentioning

confidence: 99%

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

Criscitiello

Kraev

Lange

2020

IJMS

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The bovine immune system is known for its unusual traits relating to immunoglobulin and antiviral responses. Peptidylarginine deiminases (PADs) are phylogenetically conserved enzymes that cause post-translational deimination, contributing to protein moonlighting in health and disease. PADs also regulate extracellular vesicle (EV) release, forming a critical part of cellular communication. As PAD-mediated mechanisms in bovine immunology and physiology remain to be investigated, this study profiled deimination signatures in serum and serum-EVs in Bos taurus. Bos EVs were poly-dispersed in a 70-500 nm size range and showed differences in deiminated protein cargo, compared with whole sera. Key immune, metabolic and gene regulatory proteins were identified to be post-translationally deiminated with some overlapping hits in sera and EVs (e.g., immunoglobulins), while some were unique to either serum or serum-EVs (e.g., histones). Protein-protein interaction network analysis of deiminated proteins revealed KEGG pathways common for serum and serum-EVs, including complement and coagulation cascades, viral infection (enveloped viruses), viral myocarditis, bacterial and parasitic infections, autoimmune disease, immunodeficiency intestinal IgA production, B-cell receptor signalling, natural killer cell mediated cytotoxicity, platelet activation and hematopoiesis, alongside metabolic pathways including ferroptosis, vitamin digestion and absorption, cholesterol metabolism and mineral absorption. KEGG pathways specific to EVs related to HIF-1 signalling, oestrogen signalling and biosynthesis of amino acids. KEGG pathways specific for serum only, related to Epstein-Barr virus infection, transcription mis-regulation in cancer, bladder cancer, Rap1 signalling pathway, calcium signalling pathway and ECM-receptor interaction. This indicates differences in physiological and pathological pathways for deiminated proteins in serum-EVs, compared with serum. Our findings may shed light on pathways underlying a number of pathological and anti-pathogenic (viral, bacterial, parasitic) pathways, with putative translatable value to human pathologies, zoonotic diseases and development of therapies for infections, including anti-viral therapies.

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“…Our combined analysis of proteomics data derived from SARS-CoV-2-infected cells [7] and gender-and age-dependent gene expression data derived from the GTEx dataset identified transferrin as a candidate factor, which may be involved in COVID-19-related coagulopathy. Although transferrin is an iron carrier protein that circulates and delivers iron to cells via transferrin receptor binding followed by receptor-mediated endocytosis [11,12], it promotes coagulation by ironindependent mechanisms [9]. A systematic investigation of gene products associated with the GO term "blood coagulation" did not reveal further high confidence candidates, which are likely to contribute to COVID-19-related coagulopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Transferrin is primarily produced in the liver, but also in other tissues [11][12][13][14][15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

COVID-19-related coagulopathy – Is transferrin a missing link?

McLaughlin

Bechtel

Bojkova

et al. 2020

Preprint

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SARS-CoV-2 is the causative agent of COVID-19. Severe COVID-19 disease has been associated with disseminated intravascular coagulation and thrombosis, but the mechanisms underlying COVID-19-related coagulopathy remain unknown. Since the risk of severe COVID-19 disease is higher in males than in females and increases with age, we combined proteomics data from SARS-CoV-2-infected cells with human gene expression data from the Genotype-Tissue Expression (GTEx) database to identify gene products involved in coagulation that change with age, differ in their levels between females and males, and are regulated in response to SARS-CoV-2 infection. This resulted in the identification of transferrin as a candidate coagulation promoter, whose levels increases with age and are higher in males than in females and that is increased upon SARS-CoV-2 infection. A systematic investigation of gene products associated with the GO term "blood coagulation" did not reveal further high confidence candidates, which are likely to contribute to COVID-19-related coagulopathy. In conclusion, the role of transferrin should be considered in the course of COVID-19 disease and further examined in ongoing clinic-pathological investigations.

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Transferrin and transferrin receptors update

Cited by 424 publications

References 159 publications

Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non–Small Cell Lung Cancer Cells

Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non–Small Cell Lung Cancer Cells

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

COVID-19-related coagulopathy – Is transferrin a missing link?

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