Emerging treatments in lung cancer - targeting the RLIP76 molecular transporter.
Emerging treatments in lung cancer - targeting the RLIP76 molecular transporter.
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DOI：
10.2147/lctt.s53672
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Lee S
中科院分区：
文献类型：
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作者：
Goldfinger LE;Lee S
肺癌细胞的多药耐药是肺癌治疗的一个重要障碍。对化疗药物的耐药性通常是药物从癌细胞外排的结果，由三磷酸腺苷（ATP）依赖的药物通过质膜转运介导。因此，确定癌细胞转运机制中的分子靶点可能是成功联合治疗的关键因素，同时也是化疗药物的关键因素。76 kDa的运输蛋白RLIP76 (RLIP76)，也被称为ral结合蛋白1 (RalBP1)，是一个非常有希望的肺癌治疗靶点。RLIP76是一种atp依赖的非atp结合盒（ABC）转运体，在包括许多癌细胞系在内的许多细胞中负责主要的转运功能，引起内源性代谢物和环境毒素的谷胱甘肽亲电偶联物的外排。RLIP76在大多数人体组织中表达，并在非小细胞肺癌细胞系和许多肿瘤类型中过表达。通过各种途径阻断RLIP76已被证明会增加对放疗和化疗药物的敏感性，并导致细胞凋亡。在小鼠异种移植肿瘤模型中，RLIP76阻断或消耗导致许多癌症细胞类型（包括肺癌细胞）完全和持续的消退。除了运输功能外，RLIP76还具有基于其结构域结构的许多其他细胞和生理功能，包括独特的ral结合结构域和Rho GTPase激活蛋白（RhoGAP）催化结构域以及多种信号蛋白的对接位点。RLIP76作为一种ras效应蛋白、RhoGAP蛋白和转换蛋白，在细胞内吞作用、线粒体分裂、细胞扩散和迁移、原肠形成过程中的肌动蛋白动力学和ras诱导的肿瘤发生中发挥重要作用。此外，RLIP76对肿瘤中基质细胞的功能也很重要，因为它最近被证明是实体瘤中有效的内皮细胞功能和血管生成所必需的。然而，RLIP76敲除小鼠是可以存活的，并且阻断作用似乎对小鼠体内植入的肿瘤具有选择性，这表明靶向RLIP76的药物可能在临床试验中取得成功。在这篇综述中，我们概述了RLIP76在正常细胞和癌细胞中的许多细胞和生理功能，并讨论了基于RLIP76的治疗方法在肺癌治疗中的潜力。
Multidrug resistance in lung cancer cells is a significant obstacle in the treatment of lung cancer. Resistance to chemotherapeutic agents is often the result of efflux of the drugs from cancer cells, mediated by adenosine triphosphate (ATP)-dependent drug transport across the plasma membrane. Thus, identifying molecular targets in the cancer cell transport machinery could be a key factor in successful combinatorial therapy, along with chemotherapeutic drugs. The transport protein Ral-interacting protein of 76 kDa (RLIP76), also known as Ral-binding protein 1 (RalBP1), is a highly promising target for lung cancer treatment. RLIP76 is an ATP-dependent non-ATP-binding cassette (ABC) transporter, responsible for the major transport function in many cells, including many cancer cell lines, causing efflux of glutathione-electrophile conjugates of both endogenous metabolites and environmental toxins. RLIP76 is expressed in most human tissues, and is overexpressed in non-small-cell lung cancer cell lines and in many tumor types. The blockade of RLIP76 by various approaches has been shown to increase the sensitivity to radiation and chemotherapeutic drugs, and leads to apoptosis in cells. In xenograft tumor models in mice, RLIP76 blockade or depletion results in complete and sustained regression across many cancer cell types, including lung cancer cells. In addition to its transport function, RLIP76 has many other cellular and physiological functions based on its domain structure, which includes a unique Ral-binding domain and a Rho GTPase activating protein (RhoGAP)-catalytic domain as well as docking sites for multiple signaling proteins. As a Ral effector, RhoGAP, and adapter protein, RLIP76 has been shown to play important roles in endocytosis, mitochondrial fission, cell spreading and migration, actin dynamics during gastrulation, and Ras-induced tumorigenesis. Additionally, RLIP76 is also important for stromal cell function in tumors, as it was recently shown to be required for efficient endothelial cell function and angiogenesis in solid tumors. However, RLIP76 knockout mice are viable, and blockade effects appear to be selective for implanted tumors in mice, suggesting the possibility that RLIP76-targeting drugs may be successful in clinical trials. In this review, we outline the many cellular and physiological functions of RLIP76 in normal and cancer cells, and discuss the potential for RLIP76-based therapeutics in lung cancer treatment.