Targeting mitochondrial metabolism for metastatic cancer therapy.
Targeting mitochondrial metabolism for metastatic cancer therapy.
复制标题
靶向线粒体代谢用于转移性癌症治疗。
DOI：
10.1002/mc.23436
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发表时间：
2022-09
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
原发肿瘤进化出有利于糖酵解产生ATP和抗氧化防御的代谢机制。相反，转移细胞通常依赖于线粒体呼吸和氧化磷酸化（OxPhos）。这种转移细胞对OxPhos的依赖可以通过靶向线粒体代谢的药物来利用。因此，通过多种机制起作用的治疗剂，包括激活促进活性氧（ROS）产生的信号通路和/或降低抗氧化防御，可能会升高氧化应激并抑制肿瘤细胞存活。在这篇综述中，我们将提供(1)功能选择性细胞外信号调节激酶-1/2 （ERK1/2）抑制剂通过增强ROS抑制癌细胞的机制分析，(2)线粒体ATP合酶在氧化还原调节和耐药中的作用的综述，(3)抑制ERK信号和线粒体OxPhos以减少肿瘤转移和治疗耐药的治疗目标的基本原理。我们实验室最近使用转移性黑色素瘤和乳腺癌模型的报告显示，新型合理设计的靶向ERK1/2信号和线粒体ATP合酶的治疗药物具有临床前疗效，这些药物调节ROS事件，可能预防或治疗转移性癌症。这些发现和其他研究表明，靶向肿瘤的代谢需求和脆弱性可能会抑制转移途径和肿瘤生长。利用治疗药物改变肿瘤细胞氧化平衡的方法可能对癌细胞具有选择性，并可能最终对临床疗效和安全性产生影响。阐明代谢靶向的转化潜力可能会导致发现治疗转移性癌症的新方法。
Primary tumors evolve metabolic mechanisms favoring glycolysis for ATP generation and antioxidant defenses. In contrast, metastatic cells frequently depend on mitochondrial respiration and oxidative phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be exploited using drugs that target mitochondrial metabolism. Therefore, therapeutic agents that act via diverse mechanisms, including the activation of signaling pathways that promote the production of reactive oxygen species (ROS) and/or a reduction in antioxidant defenses may elevate oxidative stress and inhibit tumor cell survival. In this review, we will provide (1) a mechanistic analysis of function-selective extracellular signal-regulated kinase-1/2 (ERK1/2) inhibitors that inhibit cancer cells through enhanced ROS, (2) a review of the role of mitochondrial ATP synthase in redox regulation and drug resistance, (3) a rationale for inhibiting ERK signaling and mitochondrial OxPhos towards the therapeutic goal of reducing tumor metastasis and treatment resistance. Recent reports from our laboratories using metastatic melanoma and breast cancer models have shown the pre-clinical efficacy of novel and rationally designed therapeutic agents that target ERK1/2 signaling and mitochondrial ATP synthase, which modulate ROS events that may prevent or treat metastatic cancer. These findings and those of others suggest that targeting a tumor’s metabolic requirements and vulnerabilities may inhibit metastatic pathways and tumor growth. Approaches that exploit the ability of therapeutic agents to alter oxidative balance in tumor cells may be selective for cancer cells and may ultimately have an impact on clinical efficacy and safety. Elucidating the translational potential of metabolic targeting could lead to the discovery of new approaches for treatment of metastatic cancer.
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影响因子：
4.8
作者：
Chen W;Mook RA Jr;Premont RT;Wang J
通讯作者：
Wang J
影响因子：
30.8
作者：
da Silva Almeida AC;Abate F;Khiabanian H;Martinez-Escala E;Guitart J;Tensen CP;Vermeer MH;Rabadan R;Ferrando A;Palomero T
通讯作者：
Palomero T
影响因子：
5.7
作者：
Bola BM;Chadwick AL;Michopoulos F;Blount KG;Telfer BA;Williams KJ;Smith PD;Critchlow SE;Stratford IJ
通讯作者：
Stratford IJ
DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
4
作者：
Adams, Drew J.;Boskovic, Zarko V.;Theriault, Jimmy R.;Wang, Alex J.;Stern, Andrew M.;Wagner, Bridget K.;Shamji, Alykhan F.;Schreiber, Stuart L.
通讯作者：
Schreiber, Stuart L.