A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth

被引：1282

作者：

Bonnet, Sebastien

Archer, Stephen L.

Allalunis-Turner, Joan

Haromy, Alois

Beaulieu, Christian

Thompson, Richard

Lee, Christopher T.

Lopaschuk, Gary D.

Puttagunta, Lakshmi

Bonnet, Sandra

Harry, Gwyneth

Hashimoto, Kyoko

Porter, Christopher J.

Andrade, Miguel A.

Thebaud, Bernard

Michelakis, Evangelos D. ^{[1
]}

机构：

[1] Univ Alberta, Pulm Hypertens Program, Edmonton, AB T6G 2B7, Canada

[2] Univ Alberta, Vasc Biol Grp, Edmonton, AB T6G 2B7, Canada

[3] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2B7, Canada

[4] Univ Alberta, Dept Oncol, Edmonton, AB T6G 2B7, Canada

[5] Univ Alberta, Dept Biomed Engn, Edmonton, AB T6G 2B7, Canada

[6] Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2B7, Canada

[7] Univ Alberta, Dept Pediat, Edmonton, AB T6G 2B7, Canada

[8] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB T6G 2B7, Canada

[9] Univ Ottawa, Ontario Genom Innovat Ctr, Ottawa Hlth Res Inst, Ottawa, ON K1N 6N5, Canada

[10] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1N 6N5, Canada

来源：

CANCER CELL | 2007年 / 11卷 / 01期

基金：

加拿大创新基金会; 加拿大健康研究院;

关键词：

D O I：

10.1016/j.ccr.2006.10.020

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (Delta Psi m) 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 Delta Psi m, 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.

引用

页码：37 / 51

页数：15

共 51 条

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