Unearthing the Janus-face cholesterogenesis pathways in cancer

Madan, Babita; Virshup, David M.; Nes, W. David; Leaver, David J.

doi:10.1016/j.bcp.2021.114611

Cited by 8 publications

(11 citation statements)

References 167 publications

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“…During cholesterol biosynthesis, squalene is oxidized and cyclized to form lanosterol, a C4-dimethyl sterol (Fig 2A-B). Conversion of lanosterol to cholesterol proceeds down two parallel routes known as the Bloch and Kandutsch-Russell (KR) pathways and involves nine distinct enzymes (18, 30, 31) (Fig 2A). One of the key steps in this process is the removal of the two methyl groups at the C4 position.…”

Section: Resultsmentioning

confidence: 99%

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling

Madan,

Wadia,

Patnaik

et al. 2023

Preprint

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Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here we report for the first time that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulates the abundance of specific C4-methyl sterols lophenol and dihydro-TMAS. Highlighting its clinical relevance, FAXDC2 is repressed in Wnt/β-catenin high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulates in the cancerous tissues and not in adjacent normal tissues. FAXDC2 links Wnts to RTK/MAPK signaling. Wnt inhibition drives increased recycling of RTKs and activation of the MAPK pathway, and this requires FAXDC2. Blocking Wnt signaling in Wnt-high cancers causes both differentiation and senescence; and this is prevented by knockout of FAXDC2. Our data shows the integration of three ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation.Abstract Figure

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Section: Resultsmentioning

confidence: 99%

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling

Madan,

Wadia,

Patnaik

et al. 2023

Preprint

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“…and select non-photosynthetic pathogenic algae ( Prototheca sp. ), cycloartenol synthase converts 2,3-oxidosqualene into cycloartenol [ 14 , 23 , 24 , 25 , 26 ], while in fungi, animals, kinetoplasts the lanosterol synthase generally converts 2,3-oxidosqualene into lanosterol [ 2 , 15 , 27 ]. As shown in Figure 2 , these protosterols are further converted to Δ 5 -sterol products with distinct canonical patterns resulting from a kinetically favored pathway that is regulated by individual enzyme substrate specificities and their corresponding turnover rates in the Archaeplastida and Amoebozoa versus the Excavata and Opisthokonta.…”

Section: For Context: Background For C24-smt and C14-sdm Enzymes In S...mentioning

confidence: 99%

“…In this review, we are interested in crucial steroidogenic enzymes that act on sterol molecules [ 1 , 2 ] to produce membrane inserts—ergosterol (eukaryotic pathogenic organisms: fungi, trypanosomes and amoebae) and cholesterol (animal hosts) [ 3 , 4 , 5 ], and the medical relevance in targeting active site structures and reaction mechanisms of sterolic enzymes notably those sensitive to substrate analogs that can bind irreversibly to combat ergosterol-dependent diseases ( Table 1 ). More specifically, this review highlights the award lecture for the sterol prize-George Schroepfer Medal presented to W.D.N.…”

Section: Introductionmentioning

confidence: 99%

Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads

Nes,

Chaudhuri,

Leaver

2024

Biomolecules

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Sterol biosynthesis via the mevalonate-isoprenoid pathway produces ergosterol (24β- methyl cholesta-5,7-dienol) necessary for growth in a wide-range of eukaryotic pathogenic organisms in eukaryotes, including the fungi, trypanosomes and amoebae, while their animal hosts synthesize a structurally less complicated product—cholesterol (cholest-5-enol). Because phyla-specific differences in sterol metabolizing enzyme architecture governs the binding and reaction properties of substrates and inhibitors while the order of sterol metabolizing enzymes involved in steroidogenesis determine the positioning of crucial chokepoint enzymes in the biosynthetic pathway, the selectivity and effectiveness of rationally designed ergosterol biosynthesis inhibitors toward ergosterol-dependent infectious diseases varies greatly. Recent research has revealed an evolving toolbox of mechanistically distinct tight-binding inhibitors against two crucial methylation-demethylation biocatalysts—the C24 sterol methyl transferase (absent from humans) and the C14-sterol demethylase (present generally in humans and their eukaryotic pathogens). Importantly for rational drug design and development, the activities of these enzymes can be selectively blocked in ergosterol biosynthesis causing loss of ergosterol and cell killing without harm to the host organism. Here, we examine recent advances in our understanding of sterol biosynthesis and the reaction differences in catalysis for sterol methylation-demethylation enzymes across kingdoms. In addition, the novelties and nuances of structure-guided or mechanism-based approaches based on crystallographic mappings and substrate specificities of the relevant enzyme are contrasted to conventional phenotypic screening of small molecules as an approach to develop new and more effective pharmacological leads.

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“…Due to the low solubility, its high level may cause coronary heart attack that can lead to death. The amphipathic property and the shape of the cholesterol molecule make it suitable as a membrane insert [ 9 ]. Cholesterol is providing both mechanical stiffness and elasticity to cells by the polar head groups of cholesterol oriented toward the polar heads of phospholipids.…”

Section: Introductionmentioning

confidence: 99%

“…Cholesterol is providing both mechanical stiffness and elasticity to cells by the polar head groups of cholesterol oriented toward the polar heads of phospholipids. The relationship of cholesterol to anticancer drugs revealed that antitumour agents selectively inhibit cholesterol biosynthetic enzymes [ 9 ]. Prokaryotic cells do not contain cholesterol but the related pentacyclic triterpenoids collectively termed hopanes.…”

Section: Introductionmentioning

confidence: 99%

Apoptotic Janus-faced mycotoxins against thoracal and breast metastases

Bánfalvi

2023

Apoptosis

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Abdominal organs (liver, kidney, spleen) are frequent targets of cancer cell invasion but their primary tumours are less known for their metastatic potential to other organs e.g. to the breast. Despite the known connection of the pathogenesis from breast cancer to liver metastasis, the study of the spread in the opposite direction has been neglected. The notion that breast cancer could be a metastasis besides being a primary tumour is based on rodents’ tumour models upon implantation of tumour cells under the capsule of the kidney or under the Glisson’s capsule of the liver of rats and mice. Tumour cells develop into a primary tumour at the site of subcutaneous implantation. The metastatic process starts with peripheral disruptions of blood vessels near the surface of primary tumours. Tumour cells released into the abdomen cross the apertures of the diaphragm, enter the thoracal lymph nodes and accumulate in parathymic lymph nodes. Abdominal colloidal carbon particles injected into the abdomen faithfully mimicked the migration of tumour cells and deposited in parathymic lymph nodes (PTNs). An explanation is provided why the connection between abdominal tumours and mammary tumours escaped attention, notably, parathymic lymph nodes in humans were referred to as internal mammary or parasternal lymph nodes. The apoptotic effect of Janus-faced cytotoxins is suggested to provide a new approach against the spread of abdominal primary tumours, and metastatic development.

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Unearthing the Janus-face cholesterogenesis pathways in cancer

Cited by 8 publications

References 167 publications

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling

Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads

Apoptotic Janus-faced mycotoxins against thoracal and breast metastases

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