Effect of Hemin and Protoporphyrin IX on the Protein-Synthesizing Activity of Human Granulocytes, Lymphocytes and Platelets

Malik, Zvi; Agam, Galila; Djaldetti, M

doi:10.1159/000207646

Cited by 13 publications

(8 citation statements)

References 10 publications

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“…To ensure the enormous output of heme biosynthesis, the supply of substrates, intermediates and end-products in the pathway is tightly regulated and precisely balanced (Hunter and Ferreira, 2011). Heme is a double-edged sword for cell growth; it is essential in the “right amount” (Cao and Dixon, 2016) and if not can be toxic (Malik and Djaldetti, 1980) via unique forms of cell death.…”

Section: Introductionmentioning

confidence: 99%

Porphyrin overdrive rewires pan-cancer cell metabolism

Adapa

Hunter

Amin

et al. 2022

Preprint

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All cancers reprogram their metabolism. In this study, we report that all cancer cells employ imbalanced and dynamic heme metabolic pathways essential for their oncogenic growth and coined the term heme overdrive. Three key characteristics define heme overdrive, i.e., cancer universality, cancer essentiality and cancer specificity. While heme overdrive is absent in diverse differentiated cells or somatic stem cells, it is present in hundreds of cancers, and is delineated in patient-derived tumor progenitor cells by single cell RNAseq. The only exception to heme overdrive in normal tissues is identified in preimplantation human embryos, where heme overdrive likely links to embryonic omnipotency. Among the major drivers are proteins involved in biosynthesis of heme intermediates (hydroxymethylbilane synthase (HMBS) and uroporphyrinogen decarboxylase (UROD)) and heme trafficking (FLVCR1). CRISPR/Cas9 editing to engineer leukemia cells with impaired heme biosynthesis steps confirmed our whole genomic data analyses that heme overdrive is linked to oncogenic states and cellular differentiation. Finally, we devised a novel bait-and-kill strategy to target this cancer metabolic vulnerability.

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Section: Introductionmentioning

confidence: 99%

Porphyrin overdrive rewires pan-cancer cell metabolism

Adapa

Hunter

Amin

et al. 2022

Preprint

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“…A recurrent theme in the 1970s and 1980s was that investigators were able to reproducibly demonstrate that platelets incorporate amino acids into protein [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. The source and specificity of protein synthesis was confirmed with several types of classic translation inhibitors [26,27,32,33,35], and one study demonstrated that an extract from oriental hornet venom blocked protein synthesis by platelets [34].…”

mentioning

confidence: 99%

Protein synthesis by platelets: historical and new perspectives

Weyrich¹,

Schwertz

Kraiss

et al. 2009

Journal of Thrombosis and Haemostasis

261

187

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Summary. In the late 1960s, numerous investigators independently demonstrated that platelets are capable of synthesizing proteins. Studies continued at a steady pace over the next 30 years and into the 21st century. Collectively, these investigations confirmed that platelets synthesize proteins and that the pattern of protein synthesis changes in response to cellular activation. More recent studies have characterized the mechanisms by which platelets synthesize proteins and have shown that protein synthesis alters the phenotype and functions of platelets. Here, we chronologically review our increased understanding of protein synthetic responses in platelets and discuss how the field may evolve over the next decade.

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“…The Hb-induced growth inhibition can be attributed to the contained heme. Heme proteins have been implicated as growth inhibitors of hamster ovary cells (Lin, Al-Dakan and Gibson 1986), erythroleukemic cells (Drexler, Gaedicke and Minowada 1986), cell membranes (Shaklai, Avissar, Rabizadeh and Shaklai 1986), and normal hematopoetic cells (Malik, Agam and Djaldetti 1979). The mechanism of heme action remains speculative at this time; although we can postulate it induces oxidant stress at the tissue level, this remains to be elucidated.…”

Section: Effect Of Hemin On Chicken Cartilage Sulfate Uptakementioning

confidence: 97%

Hemoglobin as a Direct Inhibitor of Cartilage Growth In Vitro

Vassilopoulou‐Sellin

Oyedeji²,

Foster³

et al. 1989

Horm Metab Res

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Growth retardation is a feature of several diseases associated with chronic hemolysis (i.e., uremia and the hemoglobinopathies). Although the growth failure is undoubtedly multifactorial, circulating hemoglobin (Hb) may inhibit cartilage growth directly. We tested this hypothesis using the hypophysectomized rat costal cartilage sulfation bioassay and the embryonic chicken pelvic rudiment bioassay, both very sensitive to growth factors and growth inhibitors. In the rat bioassay, Hb produced a dose-dependent inhibition of both basal and normal rat serum (NRS)-stimulated 35SO4 uptake. In the chick bioassay, NRS stimulated cartilage growth as expected, but Hb severely inhibited both basal and NRS-stimulated growth. However, after the cartilages were preincubated with Hb for 2 days, subsequent exposure to NRS allowed them to resume growth at the same rate as cartilage exposed to NRS for the entire 5 days. The growth inhibition could be accounted for by the heme contained in Hb. We conclude that Hb produces a dose-dependent and reversible inhibition of cartilage growth and may contribute to the growth retardation associated with chronic hemolytic conditions.

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Effect of Hemin and Protoporphyrin IX on the Protein-Synthesizing Activity of Human Granulocytes, Lymphocytes and Platelets

Cited by 13 publications

References 10 publications

Porphyrin overdrive rewires pan-cancer cell metabolism

Porphyrin overdrive rewires pan-cancer cell metabolism

Protein synthesis by platelets: historical and new perspectives

Hemoglobin as a Direct Inhibitor of Cartilage Growth In Vitro

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