Targeting unique metabolic properties of breast tumor initiating cells.
Normal stem cells from a variety of tissues display unique metabolic properties compared to their more differentiated progeny. However, relatively little is known about metabolic properties of cancer stem cells, also called tumor initiating cells (TICs). In this study we show that, analogous to some normal stem cells, breast TICs have distinct metabolic properties compared to nontumorigenic cancer cells (NTCs). Transcriptome profiling using RNA-Seq revealed TICs underexpress genes involved in mitochondrial biology and mitochondrial oxidative phosphorylation, and metabolic analyses revealed TICs preferentially perform glycolysis over oxidative phosphorylation compared to NTCs. Mechanistic analyses demonstrated that decreased expression and activity of pyruvate dehydrogenase (Pdh), a key regulator of oxidative phosphorylation, plays a critical role in promoting the proglycolytic phenotype of TICs. Metabolic reprogramming via forced activation of Pdh preferentially eliminated TICs both in vitro and in vivo. Our findings reveal unique metabolic properties of TICs and demonstrate that metabolic reprogramming represents a potential therapeutic strategy for targeting these cells.
Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine.
Weiguo
W
Feng
Andrew
A
Gentles
Ramesh V
RV
Nair
Min
M
Huang
Yuan
Y
Lin
Cleo Y
CY
Lee
Shang
S
Cai
Ferenc A
FA
Scheeren
Angera H
AH
Kuo
Maximilian
M
Diehn
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002469:Cell Separation; D003999:Dichloroacetic Acid / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D050259:Genes, Mitochondrial; D006019:Glycolysis; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059467:Transcriptome
D000970:Antineoplastic Agents; D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid
Breast tumor initiating cells or cancer stem cells; Dichloroacetic acid; Glycolysis Oxidative phosphorylation; Metabolic reprogramming; Warburg effect