PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer

Cell Metab. 2015 Oct 6;22(4):577-89. doi: 10.1016/j.cmet.2015.08.007. Epub 2015 Sep 10.

Abstract

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-1α activity and expression of the HIF-1α target Pyruvate dehydrogenase kinase-1 (PDK1). Silencing HIF-1α 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Carbon Isotopes / chemistry
  • Carbon Isotopes / metabolism
  • Cell Hypoxia
  • Cell Line, Tumor
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Glutamine / metabolism
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Metabolic Engineering*
  • Metabolome
  • Mice
  • Mice, Inbred BALB C
  • Oxidative Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA Interference
  • RNA, Small Interfering / metabolism

Substances

  • Carbon Isotopes
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA, Small Interfering
  • Glutamine
  • Protein-Serine-Threonine Kinases