Journal article
Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-?B impairs this drug-induced senescence
EMBO molecular medicine, Vol.5(1), pp.149-166
01/01/2013
DOI: 10.1002/emmm.201201378
PMCID: PMC3569660
PMID: 23180582
Abstract
Oncogene-induced senescence can provide a protective mechanism against tumour progression. However, production of cytokines and growth factors by senescent cells may contribute to tumour development. Thus, it is unclear whether induction of senescence represents a viable therapeutic approach. Here, using a mouse model with orthotopic implantation of metastatic melanoma tumours taken from 19 patients, we observed that targeting aurora kinases with MLN8054/MLN8237 impaired mitosis, induced senescence and markedly blocked proliferation in patient tumour implants. Importantly, when a subset of tumour-bearing mice were monitored for tumour progression after pausing MLN8054 treatment, 50% of the tumours did not progress over a 12-month period. Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-?B-related, senescence-associated secretory phenotype (SASP). Blockade of IKK beta/NF-?B led to reversal of MLN8237-induced senescence and SASP. Results demonstrate that removal of senescent tumour cells by infiltrating myeloid cells is crucial for inhibition of tumour re-growth. Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.
Details
- Title: Subtitle
- Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-?B impairs this drug-induced senescence
- Creators
- Yan Liu - Vanderbilt University Medical CenterOriana E. Hawkins - Vanderbilt University Medical CenterYingjun Su - Vanderbilt University Medical CenterAnna E. Vilgelm - Vanderbilt University Medical CenterTammy Sobolik - Vanderbilt University Medical CenterYee-Mon Thu - Vanderbilt University Medical CenterSara Kantrow - Vanderbilt University Medical CenterRyan C. Splittgerber - Vanderbilt University Medical CenterSarah Short - Vanderbilt University Medical CenterKatayoun I. Amiri - Vanderbilt University Medical CenterJeffery A. Ecsedy - Millennium Engineering and Integration (United States)Jeffery A. Sosman - Vanderbilt University Medical CenterMark C. Kelley - Vanderbilt UniversityAnn Richmond - Vanderbilt University Medical Center
- Resource Type
- Journal article
- Publication Details
- EMBO molecular medicine, Vol.5(1), pp.149-166
- DOI
- 10.1002/emmm.201201378
- PMID
- 23180582
- PMCID
- PMC3569660
- NLM abbreviation
- EMBO Mol Med
- ISSN
- 1757-4676
- eISSN
- 1757-4684
- Publisher
- Wiley
- Number of pages
- 18
- Grant note
- 2 UL1 TR000445-06 / National Center for Advancing Translational Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) UL1TR000445 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) R01FD003522 / FOOD AND DRUG ADMINISTRATION; United States Department of Health & Human Services P30 CA68485 / Vanderbilt Ingram Cancer Center P30DK058404 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) U54CA163072 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) DK058404 / Vanderbilt Digestive Disease Research Center K12 GM068543 / NIH, Institutional Research and Academic Career Development; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Tennessee Valley Healthcare System K12GM068543 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) CA116021; 5P30CA068485; T32HL07751; T32 119925; K12-CA090625 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Valvano Foundation for Cancer Research Department of Veterans Affairs; US Department of Veterans Affairs T32HL007751 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 01/01/2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420838202771
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