Details

Autor(en) / Beteiligte

• Sakuma, Stephen

Titel

Targeting Nuclear Pore Complex Assembly to Treat Cancer

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2024

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Nuclear pore complexes (NPCs) are large multi-protein channels connecting the nucleus and cytoplasm. Cancer cells, especially multidrug-resistant and aggressive tumor cells, exhibit increased NPCs, higher transport rates, and dependency on the nuclear transport system. Traditionally, targeting NPCs directly was deemed impractical due to their essential role. However, findings suggest that NPCs are long-lived structures, and that NPC formation mainly occurs during cell proliferation, suggesting that NPC formation could be inhibited, and it would preferentially reduce NPC numbers in actively dividing cells like cancer cells. This work provides evidence that inhibiting NPC formation induces cancer cell death while causing reversible cell cycle arrest in normal cells, allowing survival. Reduced NPC numbers prevented melanoma and colorectal xenograft tumor growth and induce regression. Suppression of NPC assembly affects multiple cellular processes associated with transformation, leading to cancer-specific cell death. To find a pathway that modulates this process we performed the first whole genome screen of NPC assembly regulators and confirmed that the CCR4-NOT limits the NPC assembly process by reducing global RNA levels and subsequent protein synthesis. The study demonstrates that blocking nuclear pore formation is a promising strategy for anti-neoplastic therapies and reveals a novel regulator of the process.