Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response
Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response
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DOI：
10.1158/0008-5472.can-19-0644
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发表时间：
2020-01-15
期刊：
影响因子：
11.2
通讯作者：
Kamphorst, Jurre J.
中科院分区：
文献类型：
--
作者：
McGregor, Grace H.;Campbell, Andrew D.;Kamphorst, Jurre J.
他汀类药物是广泛使用的甲羟戊酸途径抑制剂，可降低全身胆固醇水平。甲羟戊酸途径对肿瘤发生至关重要，并且在癌症中经常上调。尽管如此，他汀类药物对肿瘤进展的影响尚不明确，因此尚不清楚他汀类药物单独或联合是否可用于化疗。在这里，使用先进的质谱和同位素示踪，我们表明，他汀类药物只适度影响癌症胆固醇稳态。相反，他们显着降低了另一种下游产物线粒体电子载体辅酶Q的合成和水平，无论是在培养的癌细胞和肿瘤中。这损害了氧化磷酸化，导致严重的氧化应激。为了补偿，癌细胞上调抗氧化剂代谢途径，包括还原羧化，脯氨酸合成和胱氨酸输入。用xCT转运蛋白降低MEK抑制剂靶向胱氨酸输入，与他汀类药物组合，引起严重的肿瘤细胞死亡。因此，他汀类药物诱导的活性氧在癌细胞中的生产，可以利用在combinatorial regimen.Significance：癌细胞诱导特定的代谢途径，以减轻他汀类药物治疗引起的氧化应激增加，并针对这些途径之一协同他汀类药物产生强大的抗肿瘤反应。
Statins are widely prescribed inhibitors of the mevalonate pathway, acting to lower systemic cholesterol levels. The mevalonate pathway is critical for tumorigenesis and is frequently upregulated in cancer. Nonetheless, reported effects of statins on tumor progression are ambiguous, making it unclear whether statins, alone or in combination, can be used for chemotherapy. Here, using advanced mass spectrometry and isotope tracing, we showed that statins only modestly affected cancer cholesterol homeostasis. Instead, they significantly reduced synthesis and levels of another downstream product, the mitochondrial electron carrier coenzyme Q, both in cultured cancer cells and tumors. This compromised oxidative phosphorylation, causing severe oxidative stress. To compensate, cancer cells upregulated antioxidant metabolic pathways, including reductive carboxylation, proline synthesis, and cystine import. Targeting cystine import with an xCT transporter-lowering MEK inhibitor, in combination with statins, caused profound tumor cell death. Thus, statin-induced ROS production in cancer cells can be exploited in a combinatorial regimen.Significance: Cancer cells induce specific metabolic pathways to alleviate the increased oxidative stress caused by statin treatment, and targeting one of these pathways synergizes with statins to produce a robust antitumor response.