Inosine Monophosphate Dehydrogenase 2 (IMPDH2) Modulates Response to Therapy and Chemo-Resistance in Triple Negative Breast Cancer
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ABSTRACT:
PROVIDER: PRJNA1101442 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-01-07 | GSE264197 | GEO
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
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
Project description:Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis
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Project description:Inosine 5’-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo guanine biosynthesis and is conserved from humans to bacteria, where it is called GuaB. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important gram-negative pathogens: Acinetobacter baumannii and Escherichia coli. Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 hours. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs, and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.
2024-08-25 | GSE275261 | GEO
Project description:Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli
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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
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
Project description:Ribonucleotides serve important cellular functions as energy carriers, signaling molecules and building blocks of RNA. In eukaryotes, rRNA and tRNA synthesis in the nucleolus accounts together for over 90% of all RNA molecules. In many cancers, high proliferation rates correlated with elevation of rRNA and tRNA levels4 and nucleolar hypertrophy. However, the metabolic changes that lead to the increased nucleolar transcription and in turn foster tumorigenesis are incompletely understood. Here we show that in the highly lethal brain cancer glioblastoma (GBM), inosine monophosphate dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed. This leads to increased rRNA and tRNA synthesis and stabilization of the oncogenic GTP-binding protein nucleostemin, and enlarged and malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 reverses these malignant effects and inhibits GBM cell proliferation, whereas untransformed glia cells are unaffected. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of GBM cells even in the absence of functional p53. Our results have uncovered upregulation of IMPDH2 as a prerequisite for aberrant nucleolar function and translational capacity in GBM. This GTP metabolic reprogramming constitutes a primary event in gliomagenesis and has implications for GBM treatment and possible malignant transformation in other cancers.
2019-07-30 | GSE124727 | GEO
Project description:Physiological changes in GTP levels in live cells have never been considered a regulatory step of RAC1 activation because GTP concentrations determined by chromatography or mass spectrometry were shown to be substantially higher than the RAC1 GTP dissociation constant (RAC1-GTP Kd) determined in vitro. Here, using a combination of genetically engineered intracellular GTP sensors, recently generated by us, and RAC1 activity reporter, we demonstrate that fluctuations in GTP levels within the range of RAC1-GTP Kd, correlate with changes in RAC1 activity in live cells. We further demonstrate that RAC1 co-localize in protrusions of invading cells with the de novo guanylate biosynthesis enzymes including rate-limiting inosine monophosphate dehydrogenase 2 (IMPDH2) and guanosine monophosphate synthase (GMPS). This colocalization is partly driven by direct interaction of RAC1 with the Bateman domain of IMPDH2. Substitution of endogenous IMPDH2 with the IMPDH2 mutants incapable of binding RAC1 did not affect total intracellular GTP levels but suppressed RAC1 activity. Accordingly, targeting of IMPDH2 away from the plasma membrane did not alter total intracellular GTP pools but decreased local GTP levels in cell protrusions, downregulated RAC1 activity and decreased cell invasion. These data provide previously unrecognized mechanistic insight into the regulation of RAC1 activity by local GTP pools in live cells.
2021-11-04 | PXD028540 | Pride