The anti-cancer transition-state inhibitor MTDIA inhibits human MTAP, inducing autophagy in humanized yeast

TL;DR

This study uses a yeast model to uncover how MTDIA, a powerful anti-cancer drug, works by inhibiting MTAP and triggering autophagy.

Contribution

The study introduces a humanized yeast model to investigate MTDIA's anti-cancer mechanisms through genomic and proteomic analyses.

Findings

MTDIA inhibits MTAP and increases methylthioadenosine levels, leading to anti-tumor effects.

Genomic and proteomic analyses revealed that MTDIA affects ribosomal function and induces autophagy.

Deleting MEU1 in yeast produced similar effects, confirming it as MTDIA's target in yeast.

Abstract

Methylthioadenosine-DADMe immucillin-A (MTDIA) is a transition-state analog that potently inhibits the human protein 5′-methylthioadenosine phosphorylase (MTAP) at picomolar concentrations and elicits anti-tumor activity against lung, prostate, colon, cervical, head and neck, and triple-negative breast cancers in cell and animal models. The anti-cancer mechanisms of MTDIA involve elevated methylthioadenosine levels but are not fully understood. The yeast protein MEU1 is functionally equivalent to human MTAP. To gain further understanding, we performed chemical genetic analyses via gene deletion and GFP-tagged protein libraries in yeast that express a member of the human equilibrative nucleoside transporter (ENT) family to permit MTDIA uptake. Genomic and proteomic analyses identified genes and proteins critical to MTDIA bioactivity. Network analysis of these genes and proteins revealed an important link to ribosomal function, which was confirmed by observing reduced levels of ribosomal subunit proteins. Network analysis also implicated autophagy, which was confirmed by analyzing intracellular trafficking of GFP-Atg8 and Phloxine B viability. In yeast, a comparable effect occurred after deletion of MEU1, indicating a single target for MTDIA in yeast. Overall, our yeast model reveals specific components of the ribosome as well as induction of autophagy as integral mechanisms that mediate the bioactivity of MTDIA.

Summary: A new model system enables genomic and proteomic analyses to identify genes, proteins and pathways integral to the bioactivity of MTDIA, a potent anti-cancer transition-state analog and inhibitor of human MTAP.

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