Lack of Hemodynamic Effects After Extended Heme Synthesis Inhibition by Succinylacetone in Rats

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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“…SA has low toxicity to animals (55,56). Likewise, our data from mouse studies suggest that HSP2 is not highly toxic to mice ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 66%

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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“…Furthermore, the cell death of sscd1 seedlings is correlated with the accumulation of SUAC (Zhou et al., ). In animals, SUAC is an irreversible inhibitor of ALAD, the second enzyme in the heme biosynthetic pathway, which converts ALA to PBG (Sassa and Kappas, ; Bourque et al ., ). The accumulation of SUAC in the body fluid of patients with HT1 causes inhibition of heme synthesis (Sassa and Kappas, ; St‐Louis and Tanguay, ).…”

Section: Discussionmentioning

confidence: 97%

Loss of fumarylacetoacetate hydrolase causes light‐dependent increases in protochlorophyllide and cell death in Arabidopsis

et al. 2019

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Fumarylacetoacetate hydrolase (FAH) catalyses the final step of the tyrosine degradation pathway, which is essential to animals but was of unknown importance in plants until we found that mutation of Short-day Sensitive Cell Death1 (SSCD1), encoding Arabidopsis FAH, results in cell death under short-day conditions. The sscd1 mutant accumulates succinylacetone (SUAC), an abnormal metabolite caused by loss of FAH. Succinylacetone is an inhibitor of d-aminolevulinic acid (ALA) dehydratase (ALAD), which is involved in chlorophyll (Chl) biosynthesis. In this study, we investigated whether sscd1 cell death is mediated by Chl biosynthesis and found that ALAD activity is repressed in sscd1 and that protochlorophyllide (Pchlide), an intermediate of Chl biosynthesis, accumulates at lower levels in etiolated sscd1 seedlings. However, it was interesting that Pchlide in sscd1 might increase after transfer from light to dark and that HEMA1 and CHLH are upregulated in the light-dark transition before Pchlide levels increased. Upon re-illumination after Pchlide levels had increased, reactive oxygen species marker genes, including singlet oxygen-induced genes, are upregulated, and the sscd1 cell death phenotype appears. In addition, Arabidopsis WT seedlings treated with SUAC mimic sscd1 in decline of ALAD activity and accumulation of Pchlide as well as cell death. These results demonstrate that increase in Pchlide causes cell death in sscd1 upon re-illumination and suggest that a decline in the Pchlide pool due to inhibition of ALAD activity by SUAC impairs the repression of ALA synthesis from the light-dark transition by feedback control, resulting in activation of the Chl biosynthesis pathway and accumulation of Pchlide in the dark.

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“…Inhibition of heme synthesis in rats is associated with decreased nitric oxide production and impaired endothelium-dependent vasodilation. 161 Interestingly, expression of ALA synthase-1 is regulated by PGC-1α, 162 possibly coordinating heme synthesis with other cytoprotective responses such as mitochondrial biogenesis and expression of antioxidant enzymes.…”

Section: Heme Synthesis and Metabolism In The Endotheliummentioning

confidence: 99%

Mitochondria and Endothelial Function

Kluge

Fetterman

Vita

2013

Circulation Research

418

365

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In contrast to their role in other cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. This article provides an overview of key aspects of mitochondrial biology in endothelial cells, including subcellular location, biogenesis, dynamics, autophagy, ROS production and signaling, calcium homeostasis, regulated cell death, and heme biosynthesis. In each section, we introduce key concepts and then review studies showing the importance of that mechanism to endothelial control of vasomotor tone, angiogenesis, and inflammatory activation. We particularly highlight the small number of clinical and translational studies that have investigated each mechanism in human subjects. Finally, we review interventions that target different aspects of mitochondrial function and their effects on endothelial function. The ultimate goal of such research is the identification of new approaches for therapy. The reviewed studies make it clear that mitochondria are important in endothelial physiology and pathophysiology. A great deal of work will be needed, however, before mitochondria-directed therapies are available for the prevention and treatment of cardiovascular disease.

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Lack of Hemodynamic Effects After Extended Heme Synthesis Inhibition by Succinylacetone in Rats

Cited by 12 publications

References 38 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

Loss of fumarylacetoacetate hydrolase causes light‐dependent increases in protochlorophyllide and cell death in Arabidopsis

Mitochondria and Endothelial Function

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