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: Although previous reports demonstrated that blocking AURKA/B using small-molecule inhibitors induces widespread apoptosis in different types of human cancer (Dar et al, 2008; Gorgun et al, 2010), we observed little apoptosis in MLN8054/MLN8237-treated melanoma patient tumour implants (Supporting Information Fig S9). In vitro studies showed that while the treatment with MLN8237 markedly reduced the number of viable cells (Fig 2A), it induced apoptosis in only 25% of SK-Mel-2 cells and in <10% of cells in three other melanoma cell lines (Fig 2B).
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.