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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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Inhibition of aurora kinases induces senescence, DNA damage and SASP in patient tumour implants treated with MLN8237The tissue level of senescence in a melanoma patient implant (V35) after mice were treated with MLN8237 or vehicle was determined by β-galactosidase staining.To assess DNA damage, 53BP1 (red) was visualized by immunofluorescence and tissues were co-stained with α-tubulin (green) and DAPI (blue). A and B were analysed from multiple slides and representative images are shown.Cytokine profile of MLN8237-treated tumour tissue was analysed in tumour tissue lysates using cytokine array.The infiltrating neutrophils and macrophages were evaluated by FACS using anti-Ly-6G and F4/80 antibodies, respectively. Seven tumours were analysed from each group. Means ± SEM are shown. p-value: ****9.16945E−06; ***0.000573.
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fig06: Inhibition of aurora kinases induces senescence, DNA damage and SASP in patient tumour implants treated with MLN8237The tissue level of senescence in a melanoma patient implant (V35) after mice were treated with MLN8237 or vehicle was determined by β-galactosidase staining.To assess DNA damage, 53BP1 (red) was visualized by immunofluorescence and tissues were co-stained with α-tubulin (green) and DAPI (blue). A and B were analysed from multiple slides and representative images are shown.Cytokine profile of MLN8237-treated tumour tissue was analysed in tumour tissue lysates using cytokine array.The infiltrating neutrophils and macrophages were evaluated by FACS using anti-Ly-6G and F4/80 antibodies, respectively. Seven tumours were analysed from each group. Means ± SEM are shown. p-value: ****9.16945E−06; ***0.000573.

Mentions: Similar results were obtained upon analysis of MLN8237-treated patient tumour implants from patient V35 and V29. These data conclusively demonstrate that MLN8237 treatment induced senescence (Fig 6A and Supporting Information Fig S13), the DDR based upon the formation of 53BP1 foci after drug treatment (Fig 6B), the SASP (Fig 6C and Supporting Information Table S3), where increases in GRO (CXCL1-3), IL-8 (CXCL8), Angiogenin, IL-6 and GRO-α (CXCL1) were observed by cytokine array.


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)

Inhibition of aurora kinases induces senescence, DNA damage and SASP in patient tumour implants treated with MLN8237The tissue level of senescence in a melanoma patient implant (V35) after mice were treated with MLN8237 or vehicle was determined by β-galactosidase staining.To assess DNA damage, 53BP1 (red) was visualized by immunofluorescence and tissues were co-stained with α-tubulin (green) and DAPI (blue). A and B were analysed from multiple slides and representative images are shown.Cytokine profile of MLN8237-treated tumour tissue was analysed in tumour tissue lysates using cytokine array.The infiltrating neutrophils and macrophages were evaluated by FACS using anti-Ly-6G and F4/80 antibodies, respectively. Seven tumours were analysed from each group. Means ± SEM are shown. p-value: ****9.16945E−06; ***0.000573.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig06: Inhibition of aurora kinases induces senescence, DNA damage and SASP in patient tumour implants treated with MLN8237The tissue level of senescence in a melanoma patient implant (V35) after mice were treated with MLN8237 or vehicle was determined by β-galactosidase staining.To assess DNA damage, 53BP1 (red) was visualized by immunofluorescence and tissues were co-stained with α-tubulin (green) and DAPI (blue). A and B were analysed from multiple slides and representative images are shown.Cytokine profile of MLN8237-treated tumour tissue was analysed in tumour tissue lysates using cytokine array.The infiltrating neutrophils and macrophages were evaluated by FACS using anti-Ly-6G and F4/80 antibodies, respectively. Seven tumours were analysed from each group. Means ± SEM are shown. p-value: ****9.16945E−06; ***0.000573.
Mentions: Similar results were obtained upon analysis of MLN8237-treated patient tumour implants from patient V35 and V29. These data conclusively demonstrate that MLN8237 treatment induced senescence (Fig 6A and Supporting Information Fig S13), the DDR based upon the formation of 53BP1 foci after drug treatment (Fig 6B), the SASP (Fig 6C and Supporting Information Table S3), where increases in GRO (CXCL1-3), IL-8 (CXCL8), Angiogenin, IL-6 and GRO-α (CXCL1) were observed by cytokine array.

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