Patched1 haploinsufficiency severely impacts intermediary metabolism in the skin of Ptch1+/\u2212/ODC transgenic mice

Changzhao Li,Bharat Mishra,Levy Kopelovich,Mohammad Athar,Mahendra Kashyap,Zhiping Weng,Shaida A Andrabi,David R Bickers,Shahid M Mukhtar,Arianna L Kim

doi:10.1038/s41598-019-49470-w

Changzhao Li, Bharat Mishra + Show 8 more

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https://doi.org/10.1038/s41598-019-49470-w

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Abstract

The study of dominantly heritable cancers has provided insights about tumor development. Gorlin syndrome (GS) is an autosomal dominant disorder wherein affected individuals develop multiple basal cell carcinomas (BCCs) of the skin. We developed a murine model of Ptch1 haploinsufficiency on an ornithine decarboxylase (ODC) transgenic background (Ptch1+/−/ODCt/C57BL/6) that is more sensitive to BCCs growth as compared with Ptch1+/+/ODCt/C57BL/6 littermates. Ptch1+/−/ODCt/C57BL/6 mice show an altered metabolic landscape in the phenotypically normal skin, including restricted glucose availability, restricted ribose/deoxyribose flow and NADPH production, an accumulation of α-ketoglutarate, aconitate, and citrate that is associated with reversal of the tricarboxylic acid cycle, coupled with increased ketogenic/lipogenic activity via acetyl-CoA, 3-hydroybutyrate, and cholesterol metabolites. Also apparent was an increased content/acetylation of amino-acids, glutamine and glutamate, in particular. Accordingly, metabolic alterations due to a single copy loss of Ptch1 in Ptch1+/−/ODCt/C57BL/6 heterozygous mice may provide insights about the cancer prone phenotype of BCCs in GS patients, including biomarkers/targets for early intervention.

Highlights

The study of dominantly heritable cancers has provided insights about tumor development
Metabolites identified by the “metabolon platformTM” in the phenotypically normal skin of Ptch1+/+/ODCt/C57BL/6 and Ptch1+/−/ODCt/C57BL/6 mice comprised a total of 859 biochemicals, 727 of which were of known identity and 132 compounds were of unknown structural/functional identity
The top 10 metabolites that were found to be significantly decreased were 2-phosphglycerate, 6-phosphogluconate, N-acetylglucosamine 6-phosphate, galactonate, lactate, phosphoenolpyruvate (PEP), 3-phosphoglycerate, fructose 1,6-diphosphate/glucose 1,6-diphosphate/myo-inositol diphosphates, sedoheptulose, and glucuronate (Supplementary Table 1). The majority of these biochemicals represent key intermediates of the glycolytic and pentose phosphate pathways (PPP), suggesting a major reduction in cellular functions that regulate glucose utilization through glycolysis, including reduced ribose/deoxyribose for nucleic acids biosynthesis, as well as NADPH levels that is largely produced through the PPP

Summary

Introduction

The study of dominantly heritable cancers has provided insights about tumor development. We show that Ptch[1] haploinsufficiency affects the metabolic landscape in phenotypically normal skin of Ptch1+/−/ODCt/C57BL/6 mice, wherein loss of a single copy of Ptch[1] in these mice caused a marked reduction of glucose utilization, coupled with reversal of the tricarboxylic acid (TCA) cycle through reductive carboxylation of α-ketoglutarate via glutamate[13,14]. This metabolic shift was associated with an accelerated metabolism www.nature.com/scientificreports/. Targeting metabolites in the skin of Ptch1+/−/ODCt/C57BL/6 mice may enable potential interventional approaches of BCCs development[16,17,18]

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