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Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.

Liu Y, Hawkins OE, Su Y, Vilgelm AE, Sobolik T, Thu YM, Kantrow S, Splittgerber RC, Short S, Amiri KI, Ecsedy JA, Sosman JA, Kelley MC, Richmond A - EMBO Mol Med (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.

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Macrophage depletion impairs senescence surveillanceThe mouse melanoma line, MelA, was treated with MLN8237 for 5 days and senescence was determined by β-galactosidase staining.MelA cells were pre-treated with MLN8237 for 1 week to induce senescence. Macrophages were depleted with 1 mg of clodronate in C57BL/6 mice. One day after clodronate treatment (macrophage depletion), 5 × 106 MLN8237-pre-treated MelA cells were injected into C57BL/6 mice. Control mice were treated with liposome vehicle (n = 5). Non-pre-treated MelA cells were also injected into C57BL/6 mice with or without macrophage depletion as controls (n = 7). Tumour formation was monitored in each group of mice for 17 days.Tumour volume was measured once per week. The scatter plot shows the tumour volume for each mouse at day 8 and Day 17.
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fig07: Macrophage depletion impairs senescence surveillanceThe mouse melanoma line, MelA, was treated with MLN8237 for 5 days and senescence was determined by β-galactosidase staining.MelA cells were pre-treated with MLN8237 for 1 week to induce senescence. Macrophages were depleted with 1 mg of clodronate in C57BL/6 mice. One day after clodronate treatment (macrophage depletion), 5 × 106 MLN8237-pre-treated MelA cells were injected into C57BL/6 mice. Control mice were treated with liposome vehicle (n = 5). Non-pre-treated MelA cells were also injected into C57BL/6 mice with or without macrophage depletion as controls (n = 7). Tumour formation was monitored in each group of mice for 17 days.Tumour volume was measured once per week. The scatter plot shows the tumour volume for each mouse at day 8 and Day 17.

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.


Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.

Liu Y, Hawkins OE, Su Y, Vilgelm AE, Sobolik T, Thu YM, Kantrow S, Splittgerber RC, Short S, Amiri KI, Ecsedy JA, Sosman JA, Kelley MC, Richmond A - EMBO Mol Med (2012)

Macrophage depletion impairs senescence surveillanceThe mouse melanoma line, MelA, was treated with MLN8237 for 5 days and senescence was determined by β-galactosidase staining.MelA cells were pre-treated with MLN8237 for 1 week to induce senescence. Macrophages were depleted with 1 mg of clodronate in C57BL/6 mice. One day after clodronate treatment (macrophage depletion), 5 × 106 MLN8237-pre-treated MelA cells were injected into C57BL/6 mice. Control mice were treated with liposome vehicle (n = 5). Non-pre-treated MelA cells were also injected into C57BL/6 mice with or without macrophage depletion as controls (n = 7). Tumour formation was monitored in each group of mice for 17 days.Tumour volume was measured once per week. The scatter plot shows the tumour volume for each mouse at day 8 and Day 17.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569660&req=5

fig07: Macrophage depletion impairs senescence surveillanceThe mouse melanoma line, MelA, was treated with MLN8237 for 5 days and senescence was determined by β-galactosidase staining.MelA cells were pre-treated with MLN8237 for 1 week to induce senescence. Macrophages were depleted with 1 mg of clodronate in C57BL/6 mice. One day after clodronate treatment (macrophage depletion), 5 × 106 MLN8237-pre-treated MelA cells were injected into C57BL/6 mice. Control mice were treated with liposome vehicle (n = 5). Non-pre-treated MelA cells were also injected into C57BL/6 mice with or without macrophage depletion as controls (n = 7). Tumour formation was monitored in each group of mice for 17 days.Tumour volume was measured once per week. The scatter plot shows the tumour volume for each mouse at day 8 and Day 17.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.

Show MeSH
Related in: MedlinePlus