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
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Mentions: Similar results were obtained upon analysis of MLN8237-treated patient tumour implants from patient V35 and V29. These data conclusively demonstrate that MLN8237 treatment induced senescence (Fig 6A and Supporting Information Fig S13), the DDR based upon the formation of 53BP1 foci after drug treatment (Fig 6B), the SASP (Fig 6C and Supporting Information Table S3), where increases in GRO (CXCL1-3), IL-8 (CXCL8), Angiogenin, IL-6 and GRO-α (CXCL1) were observed by cytokine array.
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.