Repurposing simeprevir uncovers a druggable KPNB1-p65-BCL2 survival axis in cancer.
TL;DR
This study elucidates a therapeutically targetable KPNB1-p65-Bcl-2 survival axis in multiple cancers and establishes a foundation for developing next-generation KPNB1 inhibitors.
Abstract
Proper subcellular protein localization is fundamental for protein function, yet cancer cells often exploit this machinery for survival. While the nuclear import receptor KPNB1 (importin β1) is overexpressed in various cancers, its oncogenic mechanisms remain incompletely understood and its therapeutic targeting remains in infancy. Through screening of an FDA-approved compound library, we uncovered simeprevir (Sim) and lusutrombopag (Lus) as direct KPNB1 inhibitors that disrupt its import complex assembly. These compounds blocked KPNB1-mediated nuclear import of p65, thereby suppressing Bcl-2 transcription and activating mitochondrial apoptosis. Overexpression of KPNB1, p65, or Bcl-2, but not nuclear localization signal (NLS)-deleted p65, reversed the effect of Sim/Lus. Sim induced apoptosis in multiple cancer cell lines by downregulating Bcl-2 expression and suppressed A549 xenografts growth without observable toxicity. Analysis of The Cancer Genome Atlas (TCGA) datasets substantiated the clinical relevance of the KPNB1-p65-Bcl-2 axis. Our study elucidates a therapeutically targetable KPNB1-p65-Bcl-2 survival axis in multiple cancers and establishes a foundation for developing next-generation KPNB1 inhibitors.