Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Nguyen, Nhi T.; Jaramillo-Martinez, Valeria; Mathew, Marilyn; Suresh, Varshini V.; Sivaprakasam, Sathish; Bhutia, Yangzom D.; Ganapathy, Vadivel

doi:10.3390/ijms241914672

Cited by 3 publications

(2 citation statements)

References 115 publications

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“…Cancer cells are also addicted to iron and heme because of their essential role in a multitude of metabolic processes involved in energy production as well as catabolic and anabolic processes [20,21]. Some of the critical steps in heme synthesis occur within the mitochondrial matrix, including the first regulatory step in the pathway, which combines glycine with succinyl-CoA to generate δ-aminolevulinate.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth

Mathew,

Nguyen,

Bhutia

et al. 2024

Cancers

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Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves the production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in the cancer-cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways that include amino acid metabolism, one-carbon metabolism, the pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of the expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates metabolic reprogramming, which has become a hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for the development of a new generation of therapeutics to treat cancer.

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Section: Introductionmentioning

confidence: 99%

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth

Mathew,

Nguyen,

Bhutia

et al. 2024

Cancers

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“…PGRMC1 has also been reported to play a role in cellular iron homeostasis (reviewed by Nguyen et al, 2023) [ 230 ] by (i) interacting with and regulating the terminal enzyme for heme biosynthesis, ferrochelatase, thus controlling heme release [ 131 ], (ii) upregulating hepcidin expression, a peptide hormone produced by hepatocytes that plays a role in iron homeostasis [ 231 ], and (iii) being able to donate heme to apo-cytochrome b 5 (demonstrated in vitro) [ 131 ]. A recent study [ 232 ] supported previous implications of PGRMC1 in the cellular dynamics of Ca 2+ [ 233 , 234 , 235 , 236 , 237 ] by identifying a specific interaction with the endosomal two-pore channel (TPC1), shedding light on its role in regulating ER-endosomal coupling.…”

Section: Pgrmc1 Pleiotropic Effects On Cyp Activitymentioning

confidence: 99%

Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity

Barata,

Rueff,

Kranendonk

et al. 2024

JoX

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Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome b5 (cyt b5)’s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1’s involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI).

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Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic pathways to Promote Tumor Growth

Mathew,

Nguyen,

Bhutia

et al. 2023

Preprint

View full text Add to dashboard Cite

Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in cancer cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways to include amino acid metabolism, one-carbon metabolism, pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates the metabolic reprogramming which has become the hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for development of a new generation of therapeutics to treat cancer.

show abstract

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Cited by 3 publications

References 115 publications

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth

Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic pathways to Promote Tumor Growth

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