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: To extend our findings in vivo, we examined senescence (SA-β-Gal staining), DNA damage (53BP1), NF-κB activity (IκB-α) and the SASP (IL-6) in an Hs294T xenograft tumour after MLN 8237 treatment. Tumour tissues treated with MLN8237 were β-galactosidase-positive (blue) (Fig 5A), 53BP1 (red) was increased (Fig 5B, full images are in Supporting Information Fig S12), IκB-α (red) was decreased (Fig 5C) and IL-6 (red) was increased (Fig 5D).
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.