Reference: Salita T, et al. (2023) Phosphoinositide and redox dysregulation by the anticancer methylthioadenosine phosphorylase transition state inhibitor. Biochim Biophys Acta Mol Cell Biol Lipids 1868(9):159346

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Abstract


Methylthio-DADMe-immucillin-A (MTDIA) is an 86 picomolar inhibitor of 5'-methylthioadenosine phosphorylase (MTAP) with potent and specific anti-cancer efficacy. MTAP salvages S-adenosylmethionine (SAM) from 5'-methylthioadenosine (MTA), a toxic metabolite produced during polyamine biosynthesis. Changes in MTAP expression are implicated in cancer growth and development, making MTAP an appealing target for anti-cancer therapeutics. Since SAM is involved in lipid metabolism, we hypothesised that MTDIA alters the lipidomes of MTDIA-treated cells. To identify these effects, we analysed the lipid profiles of MTDIA-treated Saccharomyces cerevisiae using ultra-high resolution accurate mass spectrometry (UHRAMS). MTAP inhibition by MTDIA, and knockout of the Meu1 gene that encodes for MTAP in yeast, caused global lipidomic changes and differential abundance of lipids involved in cell signaling. The phosphoinositide kinase/phosphatase signaling network was specifically impaired upon MTDIA treatment, and was independently validated and further characterised via altered localization of proteins integral to this network. Functional consequences of dysregulated lipid metabolism included a decrease in reactive oxygen species (ROS) levels induced by MTDIA that was contemporaneous with changes in immunological response factors (nitric oxide, tumour necrosis factor-alpha and interleukin-10) in mammalian cells. These results indicate that lipid homeostasis alterations and concomitant downstream effects may be associated with MTDIA mechanistic efficacy.

Reference Type
Journal Article | Research Support, Non-U.S. Gov't
Authors
Salita T, Rustam YH, Hofferek V, Jackson M, Tollestrup I, Sheridan JP, Schramm VL, Evans GB, Reid GE, Munkacsi AB
Primary Lit For
MEU1
Additional Lit For
MSS4 | SAC1 | FAB1 | INP52 | PIS1 | VPS34 | INP53

Phenotype Annotations 10 entries for 1 gene


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GenePhenotypeExperiment TypeMutant InformationStrain BackgroundChemicalDetails
MEU1chemical compound accumulation: decreased
classical genetics null
Allele: meu1-Δ
S288C glycerophospholipidDetails: significant decrease in the glycerophospholipid content
MEU1chemical compound accumulation: decreased
classical genetics null
Allele: meu1-Δ
S288C phosphatidylethanolamineDetails: significant decrease in the total phosphatidylethanolamine levels
MEU1chemical compound accumulation: decreased
classical genetics null
Allele: meu1-Δ
S288C phosphatidylinositolDetails: significant decrease in the total phosphatidylinositol levels relative to wt; includes decreases in PI(26:0), PI(28:0), PI(30:0), PI(30:1), PI(32:1), PI(32:2), PI(33:1), PI(34:1), and PI(34:2)
MEU1chemical compound accumulation: decreased
classical genetics null
Allele: meu1-Δ
S288C diglycerideDetails: decreased abundance of diacylglyceride
MEU1chemical compound accumulation: decreased
classical genetics null
Allele: meu1-Δ
S288C ergosteryl esterDetails: decreased abundance of ergosterol ester
MEU1chemical compound accumulation: decreased
classical genetics null
Allele: meu1-Δ
S288C reactive oxygen speciesDetails: reduction in the population of cells with high ROS levels
MEU1chemical compound accumulation: increased
classical genetics null
Allele: meu1-Δ
S288C triglycerideDetails: increased abundance of triglycerides (TG(48:3), TG(50:2), and TG(50:3)) relative to wt
MEU1protein/peptide distribution: abnormal
Reporter: Pis1-GFP
classical genetics null
Allele: meu1-Δ
S288CDetails: Pis1p is mislocalized from endosomes to the vacuole
MEU1protein/peptide distribution: abnormal
Reporter: Sac1-GFP
classical genetics null
Allele: meu1-Δ
S288CDetails: Sac1p is mislocalized from the endoplasmic reticulum to the vacuole
MEU1protein/peptide distribution: abnormal
Reporter: Vps34-GFP
classical genetics null
Allele: meu1-Δ
S288CDetails: Vps34p is mislocalized from the cytoplasm to endosomes
Showing 1 to 10 of 10 entries