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Inosine Monophosphate Dehydrogenase 2 (IMPDH2) Modulates Response to Therapy and Chemo-Resistance in Triple Negative Breast Cancer

ABSTRACT: Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to occurrence of resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance in different TNBC models. Analysis of public dataset reveals elevated IMPDH2 expression to correlate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, genetic depletion or pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemoresistant lesions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264197 | GEO | 2025/01/07

REPOSITORIES: GEO

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Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Project description:Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular connections remain elusive. Here, we delve into this crosstalk using as a model triple-negative breast cancer (TNBC), a subtype often prone to DNA damage accumulation. We reveal that the de novo purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched on chromatin in TNBC when compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts and modulates Poly [ADP-ribose] polymerase 1 (PARP1) activity by controlling nuclear availability of nicotinamide adenine dinucleotide (NAD+) -a shared metabolic cofactor- to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2 that act as convergence point of nuclear metabolism and DNA damage response. # Contributed equally *Corresponding authors: sara.sdelci@crg.eu; marta.garciacao@crg.eu

2024-09-16 | GSE271269 | GEO

Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Project description:Recent studies have highlighted the critical role of metabolism in the response to DNA damage. However, the precise metabolic interactions that are set in motion to tune this fundamental process remain largely unknown. In this study, we investigated the role of nuclear metabolism in the DNA damage response using triple-negative breast cancer as a model. By comparing the chromatin-associated proteome of different breast cancer subtypes, we observed that the purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched in the chromatin of triple-negative breast cancer cells, which are often prone to DNA damage accumulation. Downregulation, depletion, or inhibition of IMPDH2 leads to accumulation of DNA damage. IMPDH2 chromatin localization is DNA damage dose dependent and happens at a late stage of the DNA damage repair. On chromatin, IMPDH2 interacts with PARP1. The enzymatic function of IMPDH2, which consumes NAD+, modulates PARP1 activity, thus mediating a pondered DNA damage response. However, forcing the nuclear localization of exogenous IMPDH2 provokes a dramatic NAD+ depletion that results in PARP1 cleavage and consequent cytoplasmic translocation, which mediates apoptosis. Our study identifies a moonlighting role for IMPDH2 in the control of nuclear ATP and NAD+ level, which fine-tune the activation of PARP1 and regulates the DNA damage response.

2024-11-28 | PXD043522 | Pride

IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency

Project description:Metabolic dysregulation is one of the most common causes of pediatric neurodegenerative disorders. However, how the disruption of ubiquitous and essential metabolic pathways predominantly affect neural tissue remains unclear. Here we use a mouse model of AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that AMPD deficiency in mice primarily leads to hippocampal dentate gyrus degeneration despite causing a generalized reduction of brain GTP levels. Remarkably, we uncover that neurodegeneration resistant regions of the hippocampus accumulate micron sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis. In contrast, IMPDH2 filaments are barely detectable in the dentate gyrus, which show a progressively neuroinflammation and neurodegeneration. Furthermore, using a human AMPD2 neural cell culture model, we show that blocking IMPDH2 polymerization with a dominant negative IMPDH2 variant impairs AMPD2 deficient neural progenitor growth. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation caused by AMPD2 deficiency, providing resistance to neurodegeneration. This data opens the possibility of exploring the involvement of IMPDH2 assembly as a therapeutic intervention for neurodegeneration.

2024-01-16 | GSE253045 | GEO

Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics.

Project description:Inosine monophosphate dehydrogenases, encoded by IMPDH1 and IMPDH2, are targets for the important immunosuppressive drug, mycophenolic acid (MPA). Variation in MPA response may result, in part, from genetic variation in IMPDH1 and IMPDH2.We resequenced IMPDH1 and IMPDH2 using DNA from 288 individuals from three ethnic groups and performed functional genomic studies of the sequence variants observed.We identified 73 single nucleotide polymorphisms (SNPs) in IMPDH1, 59 novel, and 25 SNPs, 24 novel, in IMPDH2. One novel IMPDH1 allozyme (Leu275) had 10.2% of the wild-type activity as a result of accelerated protein degradation. Decreased activity of the previously reported IMPDH2 Phe263 allozyme was primarily due to decreased protein quantity, also with accelerated degradation. These observations with regard to the functional implications of variant allozymes were supported by the IMPDH1 and IMPDH2 X-ray crystal structures. A novel IMPDH2 intron 1 SNP, G > C IVS1(93), was associated with decreased mRNA quantity, possibly because of altered transcription.These results provide insight into the nature and extent of sequence variation in the IMPDH1 and IMPDH2 genes. They also describe the influence of gene sequence variation that alters the encoded amino acids on IMPDH function and provide a foundation for future translational studies designed to correlate sequence variation in these genes with outcomes in patients treated with MPA.

| S-EPMC3010569 | biostudies-literature

Effect of deletion of Impdh2 on gene expression in the forlimbs from E12.5 embryos and osteoclasts (OCs)

Project description:Many factors are essential for skeletal development and homeostaisis. Here we report that inosine monophosphate dehydrogenase type II (Impdh2) is a key positive regulator for limb development and bone resorption. Deletion of Impdh2 in limb mesenchymal progenitors impaired the differentiation of mesenchymal cells into chondrocyte. Meanwhile, deletion of Impdh2 in osteoclast precursors results in mice an osteopetrotic phenotype via suppressing osteoclast differentiation. Our results reveal a previously unrecognized role of Impdh2 on skeletal development and homeostasis.

2023-11-30 | GSE244054 | GEO

Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis

Project description:Inosine monophosphate (IMP) plays a central role in intracellular purine metabolism. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP fundamentally alters gene expression in the liver.To assess how IMP affects inflammatory cell activation in vivo, we subjected liver, the organ containing the highest numbers of macrophages in the body, to RNAseq analyses. High quality RNA was isolated from the livers of 3 vehicle- and 3 IMP-treated endotoxemic mice and submitted for RNAseq analysis. Our analysis identified 105 genes that were differentially expressed, determined by adjusted p values (42 downregulated, 63 upregulated; padj ≤ 0.05).

2021-09-12 | GSE183880 | GEO

Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis.

Project description:Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A2A , A2B, and A3 adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-β production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.

| S-EPMC9812230 | biostudies-literature

Oxanosine Monophosphate Is a Covalent Inhibitor of Inosine 5'-Monophosphate Dehydrogenase.

Project description:Reactive nitrogen species (RNS) are produced during infection and inflammation, and the effects of these agents on proteins, DNA, and lipids are well recognized. In contrast, the effects of RNS damaged metabolites are less appreciated. 5-Amino-3-β-(d-ribofuranosyl)-3 H-imidazo-[4,5- d][1,3]oxazine-7-one (oxanosine) and its nucleotides are products of guanosine nitrosation. Here we demonstrate that oxanosine monophosphate (OxMP) is a potent reversible competitive inhibitor of IMPDH. The value of Ki varies from 50 to 340 nM among IMPDHs from five different organisms. UV spectroscopy and X-ray crystallography indicate that OxMP forms a ring-opened covalent adduct with the active site Cys (E-OxMP*). Unlike the covalent intermediate of the normal catalytic reaction, E-OxMP* does not hydrolyze, but instead recyclizes to OxMP. IMPDH inhibitors block proliferation and can induce apoptosis, so the inhibition of IMPDH by OxMP presents another potential mechanism for RNS toxicity.

| S-EPMC6467267 | biostudies-literature

IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency

Project description:IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency

| PRJNA1063698 | ENA

Effect of depletion of IMPDH1 and IMPDH2 on gene expression after DNA damage in HeLa cells

Project description:Guanosine nucleotide (GTP) serves as a pivotal purine nucleoside triphosphate, essential for DNA and RNA structure and function. Additionally, it acts as an activator for the guanine-binding protein family (G protein), participating in crucial cellular processes such as cytoskeleton rearrangement, membrane transport, protein synthesis, and signal transduction. IMPDH1 and IMPDH2 are key enzymes in the de novo synthesis of guanine nucleotides. Our research shows that they exhibit differential activities under DNA damage conditions. Specifically, IMPDH1 predominantly maintains enzymatic activity during DNA damage, facilitating GTP synthesis and cell survival. Our data indicate that following DNA damage, IMPDH1 and IMPDH2 affect distinct pathways in cells, with IMPDH1 potentially promoting the expression of homologous recombination repair proteins.

2024-07-24 | GSE265772 | GEO

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