Targeting Methionine Metabolism Reveals AMPK-SAMTOR Signaling as a Therapeutic Vulnerability in Prostate Cancer.

Prostate cancer (PCa) is not only one of the most diagnosed malignancies in men but also a leading cause of cancer-related mortality globally. PCa exhibits unique metabolic dependencies, particularly on lipids and glutamine, unlike many solid tumors, rather than glycolysis. Methionine metabolism plays a crucial role in these metabolic pathways, contributing to polyamine biosynthesis, DNA methylation, and cellular signaling processes. Here, we demonstrate that methionine deprivation induces selective vulnerability in AMPK-deficient PC3 PCa cells by disrupting SAMTOR-mTOR signaling and triggering oxidative stress, lipid depletion, and autophagic responses. Through functional and proteomic analyses, we show that SAMTOR directly interacts with p-AMPK and modulates cell fate under methionine-limited conditions. Our findings establish a mechanistic link between methionine sensing and metabolic stress signaling in PCa, offering a new avenue for targeted intervention.