期刊论文详细信息
EMBO Molecular Medicine
Targeting aurora kinases limits tumour growth through DNA damage‐mediated senescence and blockade of NF‐κB impairs this drug‐induced senescence
Yan Liu1  Oriana E. Hawkins1  Yingjun Su1  Anna E. Vilgelm1  Tammy Sobolik1  Yee-Mon Thu1  Sara Kantrow6  Ryan C. Splittgerber4  Sarah Short1  Katayoun I. Amiri4  Jeffery A. Ecsedy3  Jeffery A. Sosman2  Mark C. Kelley5 
[1] Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA;Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;Millennium Pharmaceuticals, Inc., Cambridge, MA, USA;Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA;Division of Surgical Oncology, Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA;Division of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
关键词: aurora kinase;    DNA damage;    melanoma;    NF‐κB;    senescence;   
DOI  :  10.1002/emmm.201201378
来源: Wiley
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【 摘 要 】

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-κB-related, senescence-associated secretory phenotype (SASP). Blockade of IKKβ/NF-κB 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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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