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 investigate whether therapy-induced senescence alters the SASP in melanoma cells, we examined the levels of several cytokines and chemokines secreted into the media of MLN8237-treated melanoma cells by cytokine array (Supporting Information Table S2). The results demonstrated that IL-6, IL-7, IL-10, GM-CSF, IL-8, RANTES, GRO and GRO-α were upregulated in response to drug treatment (Fig 4A). We then further tested the levels of IL-6 and IL-8 by ELISA in four melanoma cell lines (Hs294T, SK-Mel-2, SK-Mel-5 and SK-Mel-28) treated with MLN8237 or vehicle and confirmed that both IL-6 (Supporting Information Fig S11A) and IL-8 (Supporting Information Fig S11B) were increased following MLN8237 treatment.
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.