GSH and Protein Homeostasis
While GSH synthesis was required for tumor initiation, it was found that reducing GSH levels in established tumors was not sufficient to inhibit tumor growth. In this context, additional pathways provided a backup system allowing cancer cells to survive in the absence of GSH. To interrogate these support systems, a high-throughput pharmacologic screening technique was developed to study vulnerabilities in cancer cells. Denoted Multifunctional Approach to Pharmacologic Screening (MAPS, below), enables users to determine the cellular response to perturbations of hundreds of molecular pathways. Using MAPS, it was discovered that deubiquitinases (DUBs) play an integral role in maintaining protein homeostasis in the absence of GSH. The combined inhibition of GSH and DUBs in cancer cells leads to aberrant proteotoxic stress and cell death (Harris, I.S., Cell Metabolism, 2019). This discovery, using unbiased, high-throughput approaches, demonstrated a key role for GSH in the regulation of protein homeostasis.
