Abstract
<jats:p>Solid tumors acquire malignant characteristics through adaptation to the harsh tumor microenvironment. Among the hallmarks of the tumor microenvironment, extracellular acidosis has attracted increasing attention because accumulating evidence indicates that cells cultured under low pH conditions acquire multiple resistance phenotypes to anticancer drugs. However, the molecular mechanisms underlying adaptation to low pH conditions remain largely unknown. We established a cell-based high-throughput screening method to identify compounds selectively inhibiting cell growth under low pH conditions. Salinazid was identified as a hit from a chemical library, and medicinal chemistry optimization afforded a potent analog 23. Comparative proteomic profiling of human breast cancer MCF-7 cells treated or not treated with 23 under a variety of conditions revealed that adaptation to an acidic environment markedly altered the cellular response to 23. Our results suggest that ubiquitin-proteasome system (UPS)-associated processes are particularly susceptible to perturbation by 23 in cells adapted to low pH conditions. In other words, the UPS represents a potential cellular vulnerability associated with low pH adaptation, and UPS-associated homeostasis could be a therapeutic target in cancer cells adapted to acidic tumor microenvironments.</jats:p>