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.
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| Gene | Phenotype | Experiment Type | Mutant Information | Strain Background | Chemical | Details |
|---|---|---|---|---|---|---|
| MEU1 | chemical compound accumulation: decreased | classical genetics | null Allele: meu1-Δ | S288C | glycerophospholipid | Details: significant decrease in the glycerophospholipid content |
| MEU1 | chemical compound accumulation: decreased | classical genetics | null Allele: meu1-Δ | S288C | phosphatidylethanolamine | Details: significant decrease in the total phosphatidylethanolamine levels |
| MEU1 | chemical compound accumulation: decreased | classical genetics | null Allele: meu1-Δ | S288C | phosphatidylinositol | Details: 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) |
| MEU1 | chemical compound accumulation: decreased | classical genetics | null Allele: meu1-Δ | S288C | diglyceride | Details: decreased abundance of diacylglyceride |
| MEU1 | chemical compound accumulation: decreased | classical genetics | null Allele: meu1-Δ | S288C | ergosteryl ester | Details: decreased abundance of ergosterol ester |
| MEU1 | chemical compound accumulation: decreased | classical genetics | null Allele: meu1-Δ | S288C | reactive oxygen species | Details: reduction in the population of cells with high ROS levels |
| MEU1 | chemical compound accumulation: increased | classical genetics | null Allele: meu1-Δ | S288C | triglyceride | Details: increased abundance of triglycerides (TG(48:3), TG(50:2), and TG(50:3)) relative to wt |
| MEU1 | protein/peptide distribution: abnormal Reporter: Pis1-GFP | classical genetics | null Allele: meu1-Δ | S288C | Details: Pis1p is mislocalized from endosomes to the vacuole | |
| MEU1 | protein/peptide distribution: abnormal Reporter: Sac1-GFP | classical genetics | null Allele: meu1-Δ | S288C | Details: Sac1p is mislocalized from the endoplasmic reticulum to the vacuole | |
| MEU1 | protein/peptide distribution: abnormal Reporter: Vps34-GFP | classical genetics | null Allele: meu1-Δ | S288C | Details: Vps34p is mislocalized from the cytoplasm to endosomes |