癌症独特的代谢特征(有氧糖酵解)成为癌症治疗的靶向目标

A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth

　

　

 

科学家发现，线粒体- 钾K+通道轴在肿瘤中被抑制，其正常化促进细胞凋亡，抑制肿瘤生长。因此，癌症独特的代谢特征(有氧糖酵解)可能赋予细胞凋亡抗性并具有治疗靶向性。

 

与正常细胞相比, 几个人类癌症有很高的线粒体膜电位(ΔΨm)和低表达的K +通道Kv1.5,都导致细胞凋亡抵抗。

 

二氯醋酸(DCA)抑制线粒体丙酮酸脱氢酶激酶，使癌细胞从糖酵解代谢转变为葡萄糖氧化,减少ΔΨm, 增加线粒体过氧化氢,并激活所有癌细胞的Kv渠道在所有癌症，但对正常细胞没有影响;

　

　

 

DCA通过依赖于NAFT1的机制上调Kv1.5。DCA诱导细胞凋亡，减少增殖，抑制肿瘤生长，无明显毒性。siRNA模拟DCA对PDK2的分子抑制作用。线粒体- NAFT1 - Kv轴和PDK是肿瘤重要的治疗靶点;

 

口服DCA是一种很有前途的选择性抗癌药物。

　

https://s.click.taobao.com/hYsTINw

　

 

A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth

 

Summary

The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (ΔΨm) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases ΔΨm, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.

 

http://www.sciencedirect.com/science/article/pii/S1535610806003722