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: In the nude mouse model, we observed marked increases in macrophage and neutrophil recruitment to MLN8237-treated tumours (Fig 6D), where they presumably exhibit some anti-tumour activity. Athymic nude mice exhibit enhanced T-cell-independent activation of macrophages (Cheers & Waller, 1975; Mills et al, 2000), but recently CD4+T cells were implicated in the licensing of macrophages for clearance of senescent cells in immunocompetent mice (Kang et al, 2011). Due to its translational relevance, we sought to investigate the role of macrophages in the clearance of senescent melanoma cells in a fully immunocompetent mouse model. To this end, we utilized the immunocompetent C57Bl/6 mice and a spontaneously transformed mouse melanoma cell line derived from C57Bl/6 mice (MelA) (Bennett et al, 1987). MelA cells were pretreated with MLN8237 (1 µM) for 1 week to induce senescence (Fig 7A), then the drug pre-treated MelA cells or vehicle pre-treated MelA cells were injected into C57Bl/6 mice, which were either pre-treated with clodronate (to deplete macrophages) or with liposome carrier control. Eight days after senescent MelA cells were injected into mice, tumour nodules were present in 5/5 macrophage-depleted mice. In contrast, for the mice where macrophages were not depleted, tumour growth was observed in only one out of five mice (Fig 7B) injected with senescent MelA cells. After 17 days, more tumours developed in both groups (Fig 7B). Non-senescent (drug vehicle pre-treated) MelA cells formed tumours in all mice and the mean tumour volume was much greater than in the MLN8237-pretreated senescent MelA cells. However, macrophage depletion did not affect the tumour development in vehicle pretreated tumours (8 days p = 0.7222; 17 days p = 0.9405; Fig 7C). These data suggest that macrophages recruited into the tumour in response to SASP exhibit anti-tumour activity in vivo and consequently slow tumour growth. In contrast, non-senescent tumour cells appear to retain a type of immune privilege, escaping macrophage-mediated tumour surveillance.
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.