BUB1 regulates cell proliferation and apoptosis in cervical cancer by AKT signaling and autophagosome-lysosome fusion via ACTN1.

Cervical cancer (CC) is the fourth most common cancer in women worldwide. New therapeutic targets are urgently needed considering the inadequacy of current treatments. In this study, we investigated the role of budding uninhibited by benzimidazoles 1 (BUB1) in CC and identified a dual mechanism through which BUB1 promotes tumor progression. BUB1 interacted with α-actinin 1 (ACTN1) and regulated its subcellular distribution: BUB1 maintained ACTN1 at focal adhesions to sustain AKT activation, while facilitating ACTN1-positive comet tail-propelled autophagosome trafficking toward lysosomes. Autophagosome accumulation elevated reactive oxygen species (ROS), which causally contributed to apoptosis, as demonstrated by NAC rescue experiments. Kinase-dead BUB1 failed to rescue these phenotypes. Furthermore, kinase inhibitor of BUB1, 2OH-BNPP1, phenocopied the ACTN1 intracellular localization of BUB1 knockdown, confirming the requirement for BUB1 kinase activity. 2OH-BNPP1 treatment significantly reduced the growth of subcutaneous xenograft tumors, highlighting the potential of BUB1 as a promising therapeutic target for CC.