PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer

被引：540

作者：

Dupuy, Fanny ^{[1
,2
]}

Tabaries, Sebastien ^{[1
,3
]}

Andrzejewski, Sylvia ^{[1
,2
]}

Dong, Zhifeng ^{[1
,3
]}

Blagih, Julianna ^{[1
,4
]}

Annis, Matthew G. ^{[1
,3
]}

Omeroglu, Atilla ^{[5
]}

Gao, Dongxia ^{[6
]}

Leung, Samuel ^{[6
]}

Amir, Eitan ^{[7
]}

Clemons, Mark ^{[8
]}

Aguilar-Mahecha, Adriana ^{[9
]}

Basik, Mark ^{[9
]}

Vincent, Emma E. ^{[1
,4
]}

St-Pierre, Julie ^{[1
,2
]}

Jones, Russell G. ^{[1
,4
]}

Siegel, Peter M. ^{[1
,2
,3
]}

机构：

[1] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada

[2] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada

[3] McGill Univ, Dept Med, Montreal, PQ H3A 1A3, Canada

[4] McGill Univ, Dept Physiol, Montreal, PQ H3A 1A3, Canada

[5] McGill Univ, Ctr Hlth, Dept Pathol, Montreal, PQ H4A 3J1, Canada

[6] Univ British Columbia, Dept Pathol & Lab Med, Genet Pathol Evaluat Ctr, Vancouver, BC V6H 3Z6, Canada

[7] Univ Toronto, Dept Med, Toronto, ON M5G 2M9, Canada

[8] Ottawa Hosp, Ctr Canc, Div Med Oncol, Ottawa, ON K1H 8L6, Canada

[9] Sir Mortimer B Davis Jewish Hosp, Segal Canc Ctr, Montreal, PQ H3T 1E2, Canada

来源：

CELL METABOLISM | 2015年 / 22卷 / 04期

基金：

加拿大健康研究院;

关键词：

MOUSE MAMMARY-TUMOR; GLUTAMINE-METABOLISM; GROWTH; CELLS; HYPOXIA; DICHLOROACETATE; TRANSFORMATION; ENERGY; AMPK;

D O I：

10.1016/j.cmet.2015.08.007

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Metabolic reprogramming is a hallmark of cellular transformation, yet little is known about metabolic changes that accompany tumor metastasis. Here we show that primary breast cancer cells display extensive metabolic heterogeneity and engage distinct metabolic programs depending on their site of metastasis. Liver-metastatic breast cancer cells exhibit a unique metabolic program compared to bone-or lung-metastatic cells, characterized by increased conversion of glucose-derived pyruvate into lactate and a concomitant reduction in mitochondrial metabolism. Liver-metastatic cells displayed increased HIF-1 alpha activity and expression of the HIF-1 alpha target Pyruvate dehydrogenase kinase-1 (PDK1). Silencing HIF-1 alpha reversed the glycolytic phenotype of liver-metastatic cells, while PDK1 was specifically required for metabolic adaptation to nutrient limitation and hypoxia. Finally, we demonstrate that PDK1 is required for efficient liver metastasis, and its expression is elevated in liver metastases from breast cancer patients. Our data implicate PDK1 as a key regulator of metabolism and metastatic potential in breast cancer.

引用

页码：577 / 589

页数：13

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