1. Regulation of volume-regulated anion channels alters sensitivity to platinum chemotherapy.
- Author
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Feldman LER, Mohapatra S, Jones RT, Scholtes M, Tilton CB, Orman MV, Joshi M, Deiter CS, Broneske TP, Qu F, Gutierrez C, Ye H, Clambey ET, Parker S, Mahmoudi T, Zuiverloon T, Costello JC, and Theodorescu D
- Subjects
- Humans, Cell Line, Tumor, Neoplasms drug therapy, Neoplasms metabolism, Neoplasms pathology, Neoplasms genetics, Aminopeptidases metabolism, Aminopeptidases genetics, Animals, Gene Expression Regulation, Neoplastic drug effects, Cisplatin pharmacology, Drug Resistance, Neoplasm genetics, Antineoplastic Agents pharmacology
- Abstract
Cisplatin-based chemotherapy is used across many common tumor types, but resistance reduces the likelihood of long-term survival. We previously found the puromycin-sensitive aminopeptidase, NPEPPS, as a druggable driver of cisplatin resistance in vitro and in vivo and in patient-derived organoids. Here, we present a general mechanism where NPEPPS interacts with the volume-regulated anion channels (VRACs) to control cisplatin import into cells and thus regulate cisplatin response across a range of cancer types. We also find the NPEPPS/VRAC gene expression ratio is a predictive measure of cisplatin response in multiple cancer cohorts, showing the broad applicability of this mechanism. Our work describes a specific mechanism of cisplatin resistance, which, given the characteristics of NPEPPS as a drug target, has the potential to improve cancer patient outcomes. In addition, we describe an intracellular mechanism regulating VRAC activity, which is critical for volume regulation in normal cells - a finding with functional implications beyond cancer.
- Published
- 2024
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