Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.
Bottom Line: Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-κB-related, senescence-associated secretory phenotype (SASP).Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP.Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.Show MeSH
Related in: MedlinePlus
Mentions: To address the significance of NF-κB activation on treatment outcome, we knocked down IKKβ to reduce NF-κB activity and observed that aurora kinase inhibitor-induced senescence was impaired (Fig 8A). IKKβ stable-knockdown cells gave rise to a similar phenotype (Supporting Information Fig S14). We also confirmed our results using the IKKβ inhibitor BMS-345541 (10 µM) to block the NF-κB p65 pathway (Fig 8B). When IKKβ activity was suppressed, the MLN8237-induced SASP was decreased (Fig 8C), polyploidy was reduced (Fig 8D), and less senescence was observed (Fig 8E). Although targeting IKKβ/NF-κB with BMS-345541 induces apoptosis in melanoma cells (Yang et al, 2006b), we did not observe synergistic effects on cell growth/survival when BMS345541 was combined with MLN8237 in vitro (Fig 8F), likely because blocking IKKβ reduces the induction of senescence by MLN8237, so the effect of combined treatment is largely the result of apoptosis induction by inhibition of IKKβ.
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.