Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment.
Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment.
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DOI：
10.1016/j.freeradbiomed.2014.10.860
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发表时间：
2015-02
影响因子：
7.4
通讯作者：
Stevens, Brett M.
中科院分区：
文献类型：
--
作者：
Noble, Mark;Mayer-Proeschel, Margot;Li, Zaibo;Dong, Tiefei;Cui, Wanchang;Proeschel, Christoph;Ambeskovic, Ibro;Dietrich, Joerg;Han, Ruolan;Yang, Yin Miranda;Folts, Christopher;Stripay, Jennifer;Chen, Hsing-Yu;Stevens, Brett M.
关键词：
这篇综述讨论了一个独特的发现路径开始与新的发现氧化还原调节的前体细胞和信号通路的功能和识别的一种新的机制，相对较小的变化，氧化还原状态可以控制整个信号网络，调节自我更新，分化和生存。这项工作的核心途径，氧化还原/Fyn/c-Cbl（RFC）途径，将氧化状态的小幅增加转化为c-Cbl泛素连接酶的泛激活，该连接酶控制多种受体和其他在前体细胞和癌细胞功能中至关重要的蛋白质。将RFC途径的工作与试图了解全身化疗如何导致神经系统问题的尝试相结合，发现胶质母细胞瘤（GBM）和基底样乳腺癌（BLBC）分别通过改变细胞骨架调节剂Cool-1/βpix和Cdc 42的利用来抑制c-Cbl功能。抑制这些蛋白质以恢复正常的c-Cbl功能抑制癌细胞分裂，增加对化疗的敏感性，破坏GBM和BLBC中的肿瘤起始细胞（TIC）活性，控制多种关键TIC调节剂，并且还允许靶向非TIC。此外，这些操作不会增加化学敏感性或抑制非转化细胞的分裂。正常c-Cbl功能的恢复还允许更有效地利用他莫昔芬的雌激素受体-α（ERα）非依赖性活性来激活RFC途径并靶向ERα阴性癌细胞。因此，我们的工作提供了一种发现策略，揭示了无法通过标准遗传学分析推断的机制和治疗靶点，这些分析无法揭示对我们的发现至关重要的代谢信息，同种型转变，蛋白质活化，蛋白质复合物和蛋白质降解。
This review discusses a unique discovery path starting with novel findings on redox regulation of precursor cell and signaling pathway function and identification of a new mechanism by which relatively small changes in redox status can control entire signaling networks that regulate self-renewal, differentiation, and survival. The pathway central to this work, the redox/Fyn/c-Cbl (RFC) pathway, converts small increases in oxidative status to pan-activation of the c-Cbl ubiquitin ligase, which controls multiple receptors and other proteins of central importance in precursor cell and cancer cell function. Integration of work on the RFC pathway with attempts to understand how treatment with systemic chemotherapy causes neurological problems led to the discovery that glioblastomas (GBMs) and basal-like breast cancers (BLBCs) inhibit c-Cbl function through altered utilization of the cytoskeletal regulators Cool-1/βpix and Cdc42, respectively. Inhibition of these proteins to restore normal c-Cbl function suppresses cancer cell division, increases sensitivity to chemotherapy, disrupts tumor-initiating cell (TIC) activity in GBMs and BLBCs, controls multiple critical TIC regulators, and also allows targeting of non-TICs. Moreover, these manipulations do not increase chemosensitivity or suppress division of nontransformed cells. Restoration of normal c-Cbl function also allows more effective harnessing of estrogen receptor-α (ERα)-independent activities of tamoxifen to activate the RFC pathway and target ERα-negative cancer cells. Our work thus provides a discovery strategy that reveals mechanisms and therapeutic targets that cannot be deduced by standard genetics analyses, which fail to reveal the metabolic information, isoform shifts, protein activation, protein complexes, and protein degradation critical to our discoveries.
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影响因子：
--
作者：
Acharya A;Das I;Chandhok D;Saha T
通讯作者：
Saha T
影响因子：
50.3
作者：
Binda E;Visioli A;Giani F;Lamorte G;Copetti M;Pitter KL;Huse JT;Cajola L;Zanetti N;DiMeco F;De Filippis L;Mangiola A;Maira G;Anile C;De Bonis P;Reynolds BA;Pasquale EB;Vescovi AL
通讯作者：
Vescovi AL
影响因子：
3.5
作者：
BECK, J;RONDOT, P;WIETZERBIN, J
通讯作者：
WIETZERBIN, J
影响因子：
45.3
作者：
Ahles, TA;Saykin, AJ;Silberfarb, PM
通讯作者：
Silberfarb, PM
影响因子：
4.8
作者：
Abe, JI;Okuda, M;Berk, BC
通讯作者：
Berk, BC