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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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Related in: MedlinePlus

Inhibition of aurora kinases induces senescence, DNA damage and IL-6 in vivoA. The tissue level of senescence in an Hs294T xenograft treated with MLN8237 or vehicle control was determined by β-galactosidase staining.B–D. Tissue levels of 53BP1, α-tubulin, IκB-α and IL-6 in an Hs294T xenograft treated with MLN8237 or vehicle control were visualized by immunofluorescence co-staining with DAPI. Representative micrographs are shown from triplicate experiments.
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fig05: Inhibition of aurora kinases induces senescence, DNA damage and IL-6 in vivoA. The tissue level of senescence in an Hs294T xenograft treated with MLN8237 or vehicle control was determined by β-galactosidase staining.B–D. Tissue levels of 53BP1, α-tubulin, IκB-α and IL-6 in an Hs294T xenograft treated with MLN8237 or vehicle control were visualized by immunofluorescence co-staining with DAPI. Representative micrographs are shown from triplicate experiments.

Mentions: To extend our findings in vivo, we examined senescence (SA-β-Gal staining), DNA damage (53BP1), NF-κB activity (IκB-α) and the SASP (IL-6) in an Hs294T xenograft tumour after MLN 8237 treatment. Tumour tissues treated with MLN8237 were β-galactosidase-positive (blue) (Fig 5A), 53BP1 (red) was increased (Fig 5B, full images are in Supporting Information Fig S12), IκB-α (red) was decreased (Fig 5C) and IL-6 (red) was increased (Fig 5D).


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 IL-6 in vivoA. The tissue level of senescence in an Hs294T xenograft treated with MLN8237 or vehicle control was determined by β-galactosidase staining.B–D. Tissue levels of 53BP1, α-tubulin, IκB-α and IL-6 in an Hs294T xenograft treated with MLN8237 or vehicle control were visualized by immunofluorescence co-staining with DAPI. Representative micrographs are shown from triplicate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Inhibition of aurora kinases induces senescence, DNA damage and IL-6 in vivoA. The tissue level of senescence in an Hs294T xenograft treated with MLN8237 or vehicle control was determined by β-galactosidase staining.B–D. Tissue levels of 53BP1, α-tubulin, IκB-α and IL-6 in an Hs294T xenograft treated with MLN8237 or vehicle control were visualized by immunofluorescence co-staining with DAPI. Representative micrographs are shown from triplicate experiments.
Mentions: To extend our findings in vivo, we examined senescence (SA-β-Gal staining), DNA damage (53BP1), NF-κB activity (IκB-α) and the SASP (IL-6) in an Hs294T xenograft tumour after MLN 8237 treatment. Tumour tissues treated with MLN8237 were β-galactosidase-positive (blue) (Fig 5A), 53BP1 (red) was increased (Fig 5B, full images are in Supporting Information Fig S12), IκB-α (red) was decreased (Fig 5C) and IL-6 (red) was increased (Fig 5D).

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