| Autor: |
Robert T. Jones, Andrew Goodspeed, Saswat Mohapatra, Lily Elizabeth Feldman, Mathijs Scholtes, Hedvig Vekony, Annie Jean, Charlene B. Tilton, Michael V. Orman, Cailin Deiter, Nathaniel Xander, Stephanie Araki, Molishree Joshi, Mahmood Javaid, Eric T. Clambey, Ryan Layer, Teemu D. Laajala, Sarah Parker, Tahlita Zuiverloon, Dan Theodorescu, James C. Costello |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.03.04.433676 |
| Popis: |
Despite routine platinum-based chemotherapeutic use in cancer treatment, there remains a need to improve efficacy and patient selection. Using multi-omic assessment of cisplatin responsive and resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified NPEPPS, the puromycin-sensitive aminopeptidase as a novel driver of cisplatin resistance. Volume-regulated anion channels (VRACs) have been shown to directly import the majority of intracellular cisplatin. Here, we show that the mechanism of NPEPPS-mediated cisplatin resistance is by binding to VRACs and blocking the import of cisplatin into the cell. We show that NPEPPS depletion increased intracellular cisplatin and made cisplatin-resistant cells more responsive to cisplatin in vitro and in vivo. Overexpression of NPEPPS in cisplatin-sensitive cells decreased intracellular cisplatin and resulted in increased treatment resistance. The same results also hold for carboplatin. Our findings describe the first mechanism by which VRACs can be targeted to control the import of cisplatin and carboplatin. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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