Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation
Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation
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DOI：
10.1074/jbc.ra117.001469
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发表时间：
2018-09-21
影响因子：
4.8
通讯作者：
Dwinell, Michael B.
中科院分区：
文献类型：
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作者：
Boyle, Kathleen A.;Van Wickle, Jonathan;Dwinell, Michael B.
KRAS原癌基因突变存在于50%的结直肠癌中，并且越来越多地与一线生物药物的化疗耐药性相关。越来越多的证据表明，过度活跃的KRAS突变在癌细胞中从氧化磷酸化到有氧糖酵解的代谢重编程中起着关键作用。在这里，我们试图利用癌细胞线粒体的更负的膜电位作为干扰含KRAS变体和KRAS WT结直肠癌细胞中能量代谢的未开发途径。测定线粒体功能、细胞内ATP水平、细胞摄取、能量传感器信号传导和对癌细胞增殖的功能影响。3-羧甲基戊酰氮氧化物（Mito-CP）和Mito-Metastrin，两种靶向KRAS的化合物，在KRAS WT和含KRAS变体的结肠癌细胞中耗尽细胞内ATP水平并持续抑制ATP相关的氧消耗，对非转化的肠上皮细胞仅具有有限的影响。这些抗增殖作用反映了AMP活化蛋白激酶（AMPK）的活化和磷酸化介导的mTOR靶核糖体蛋白S6激酶B1（RPS 6 KB 1或p70 S6 K）的抑制。此外，Mito-CP和Mito-Metastatin从mTOR介导的抑制中释放Unc-51样自噬激活激酶1（ULK 1），影响线粒体形态，降低线粒体膜电位，所有这些都是线粒体自噬的指标。AMPK信号级联的药理学抑制减轻了Mito-CP和Mito-Metastrophic的抗增殖作用。这是第一次证明选择性靶向线粒体的药物诱导癌细胞的线粒体自噬。用靶向药物靶向生物能量代谢以刺激线粒体自噬为KRAS WT和过度活跃的表达mu的结肠癌的治疗干预提供了一种有吸引力的方法。
Mutations in the KRAS proto-oncogene are present in 50% of all colorectal cancers and are increasingly associated with chemotherapeutic resistance to frontline biologic drugs. Accumulating evidence indicates key roles for overactive KRAS mutations in the metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis in cancer cells. Here, we sought to exploit the more negative membrane potential of cancer cell mitochondria as an untapped avenue for interfering with energy metabolism in KRAS variant-containing and KRAS WT colorectal cancer cells. Mitochondrial function, intracellular ATP levels, cellular uptake, energy sensor signaling, and functional effects on cancer cell proliferation were assayed. 3-Carboxyl proxyl nitroxide (Mito-CP) and Mito-Metformin, two mitochondria-targeted compounds, depleted intracellular ATP levels and persistently inhibited ATP-linked oxygen consumption in both KRAS WT and KRAS variant-containing colon cancer cells and had only limited effects on nontransformed intestinal epithelial cells. These anti-proliferative effects reflected the activation of AMP-activated protein kinase (AMPK) and the phosphorylation-mediated suppression of the mTOR target ribosomal protein S6 kinase B1 (RPS6KB1 or p70S6K). Moreover, Mito-CP and Mito-Metformin released Unc-51-like autophagy-activating kinase 1 (ULK1) from mTOR-mediated inhibition, affected mitochondrial morphology, and decreased mitochondrial membrane potential, all indicators of mitophagy. Pharmacological inhibition of the AMPK signaling cascade mitigated the anti-proliferative effects of Mito-CP and Mito-Metformin. This is the first demonstration that drugs selectively targeting mitochondria induce mitophagy in cancer cells. Targeting bioenergetic metabolism with mitochondria-targeted drugs to stimulate mitophagy provides an attractive approach for therapeutic intervention in KRAS WT and overactive mutant-expressing colon cancer.