Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.
Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.
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DOI：
10.1002/emmm.201201378
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发表时间：
2013-01
影响因子：
11.1
通讯作者：
Richmond, Ann
中科院分区：
文献类型：
--
作者：
Liu, Yan;Hawkins, Oriana E.;Su, Yingjun;Vilgelm, Anna E.;Sobolik, Tammy;Thu, Yee-Mon;Kantrow, Sara;Splittgerber, Ryan C.;Short, Sarah;Amiri, Katayoun I.;Ecsedy, Jeffery A.;Sosman, Jeffery A.;Kelley, Mark C.;Richmond, Ann
癌基因诱导的衰老可以提供针对肿瘤进展的保护机制。然而，衰老细胞产生的细胞因子和生长因子可能有助于肿瘤的发展。因此，目前尚不清楚诱导衰老是否代表一种可行的治疗方法。在此，使用从19例患者中取出的转移性黑色素瘤原位植入小鼠模型，我们观察到MLN 8054/MLN 8237靶向极光激酶损害有丝分裂，诱导衰老并显著阻断患者肿瘤植入物的增殖。重要的是，当暂停MLN 8054治疗后监测荷瘤小鼠亚组的肿瘤进展时，50%的肿瘤在12个月内没有进展。机制分析表明，抑制极光激酶诱导多倍体和ATM/Chk 2 DNA损伤反应，介导衰老和NF-κ B相关的衰老相关分泌表型（SASP）。阻断IKKβ/NF-κB可逆转MLN 8237诱导的衰老和SASP。结果表明，通过浸润骨髓细胞去除衰老肿瘤细胞对于抑制肿瘤再生长至关重要。总之，这些数据表明，诱导衰老，加上免疫监视，可以限制黑色素瘤的生长。
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.
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影响因子：
50.3
作者：
Jackson JG;Pant V;Li Q;Chang LL;Quintás-Cardama A;Garza D;Tavana O;Yang P;Manshouri T;Li Y;El-Naggar AK;Lozano G
通讯作者：
Lozano G
影响因子：
4
作者：
Campisi, Judith
通讯作者：
Campisi, Judith
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.
DOI：
10.1073/pnas.211053698
发表时间：
2001-10-09
影响因子：
11.1
作者：
Krtolica, A;Parrinello, S;Campisi, J
通讯作者：
Campisi, J