ROS-PIASγ cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors.
ROS-PIASγ cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors.
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DOI：
10.1038/cddis.2013.534
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发表时间：
2014-01-23
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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根据现有的关于ATM在治疗耐药中的作用的知识，本研究旨在确定影响ATM在化疗耐药和化疗敏感之间摇摆的分子机制。我们观察到肿瘤的氧化还原状态是atm依赖的“抗凋亡”分子开关的主要决定因素。在基因毒性损伤低活性氧（ROS）条件下，ATM/ sumoylatedikkγ相互作用诱导NFκB活化，抑制JNK介导的凋亡，而增加细胞ROS恢复ATM/JNK凋亡信号。对上游缺失环节的研究表明，高ROS诱导PIASγ氧化和泛素介导的PIASγ降解，从而破坏PIASγ-IKKγ串扰，这是IKKγ酰化和随后的NFκB激活的先决条件。pias γ介导的电阻通路中断向ATM/JNK促死亡电路传递ATM信号。这些体外结果也转化为敏感和耐药的异体肿瘤移植小鼠模型，在PIASγ敲除肿瘤中，低ros诱导的耐药被抑制，而其过表达抑制高ros依赖性的凋亡信号。总的来说，我们的研究发现了细胞ROS和PIASγ在调节atm介导的耐药肿瘤的化学致敏中的一个未被认识但关键的组合功能。因此，在未来的基因毒性治疗中，利用ROS上调抑制PIASγ的治疗策略可能有助于消除nfκ b介导的肿瘤耐药问题。
With the existing knowledge of ATM's role in therapeutic resistance, the present study aimed at identifying the molecular mechanisms that influence ATM to oscillate between chemoresistance and chemosensitivity. We observed that the redox status of tumors functions as a major determinant of ATM-dependent ‘resistance-to-apoptosis' molecular switch. At a low reactive oxygen species (ROS) condition during genotoxic insult, the ATM/sumoylated-IKKγ interaction induced NFκB activation that resisted JNK-mediated apoptosis, whereas increasing cellular ROS restored ATM/JNK apoptotic signaling. A search for the upstream missing link revealed that high ROS induces oxidation and ubiquitin-mediated degradation of PIASγ, thereby disrupting PIASγ-IKKγ cross talk, a pre-requisite for IKKγ sumoylation and subsequent NFκB activation. Interruption in the PIASγ-mediated resistance pathway channels ATM signaling toward ATM/JNK pro-death circuitry. These in vitro results also translated to sensitive and resistant tumor allograft mouse models in which low ROS-induced resistance was over-ruled in PIASγ knockout tumors, while its overexpression inhibited high ROS-dependent apoptotic cues. Cumulatively, our findings identified an unappreciated yet critical combinatorial function of cellular ROS and PIASγ in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIASγ during genotoxic therapy may, in future, help to eliminate the problems of NFκB-mediated tumor drug resistance.
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影响因子：
8.8
作者：
Kozakai, N.;Kikuchi, E.;Hasegawa, M.;Suzuki, E.;Ide, H.;Miyajima, A.;Horiguchi, Y.;Nakashima, J.;Umezawa, K.;Shigematsu, N.;Oya, M.
通讯作者：
Oya, M.
DOI：
10.1007/978-1-60327-530-9_10
发表时间：
2009-01-01
期刊：
INFLAMMATION AND CANCER: METHODS AND PROTOCOLS, VOL 2: MOLECULAR ANALYSIS AND PATHWAYS
影响因子：
--
作者：
Mauro, Claudio;Zazzeroni, Francesca;Franzoso, Guido
通讯作者：
Franzoso, Guido
影响因子：
3.5
作者：
Adhikary, Arghya;Mohanty, Suchismita;Das, Tanya
通讯作者：
Das, Tanya
影响因子：
4.8
作者：
Chakraborty, Juni;Banerjee, Shuvomoy;Sa, Gaurisankar
通讯作者：
Sa, Gaurisankar
影响因子：
5.3
作者：
Guo, GZ;Yan-Sanders, Y;Li, JJ
通讯作者：
Li, JJ