Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop

Abstract Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) an upstream regulator of CSC-associated genes in non-small cell lung cancer cells, suggest a target for CSC elimination. TSPYL5 elevation is driven by AKT-dependent phosphorylation at threonine-120 stabilization via inhibiting its ubiquitination. TSPYL5-pT120 also induces nuclear translocation functions transcriptional activator genes, ALDH1 CD44 . Also, suppresses the transcription PTEN , negative PI3K signaling. maintains persistent CSC-like characteristics activation positive feedback loop consisting AKT/TSPYL5/PTEN signaling pathway. Accordingly, elimination can block aberrant cyclic TSPYL5-mediated stemness regulation. Our study suggests be effective therapy-resistant cancer.