Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells.
We have previously suggested that ketone body metabolism is critical for tumor progression and metastasis. Here, using a co-culture system employing human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts, we provide new evidence to directly support this hypothesis. More specifically, we show that the enzymes required for ketone body production are highly upregulated within cancer-associated fibroblasts. This appears to be mechanistically controlled by the stromal expression of caveolin-1 (Cav-1) and/or serum starvation. In addition, treatment with ketone bodies (such as 3-hydroxy-butyrate, and/or butanediol) is sufficient to drive mitochondrial biogenesis in human breast cancer cells. This observation was also validated by unbiased proteomic analysis. Interestingly, an MCT1 inhibitor was sufficient to block the onset of mitochondrial biogenesis in human breast cancer cells, suggesting a possible avenue for anticancer therapy. Finally, using human breast cancer tumor samples, we directly confirmed that the enzymes associated with ketone body production (HMGCS2, HMGCL and BDH1) were preferentially expressed in the tumor stroma. Conversely, enzymes associated with ketone re-utilization (ACAT1) and mitochondrial biogenesis (HSP60) were selectively associated with the epithelial tumor cell compartment. Our current findings are consistent with the "two-compartment tumor metabolism" model. Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers.
The Jefferson Stem Cell Biology and Regenerative Medicine Center, Department of Stem Cell Biology & Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Ubaldo E
UE
Martinez-Outschoorn
Zhao
Z
Lin
Diana
D
Whitaker-Menezes
Anthony
A
Howell
Michael P
MP
Lisanti
Federica
F
Sotgia
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018834:Chaperonin 60 / Q000378:metabolism; D018920:Coculture Techniques; D003373:Coumaric Acids / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007657:Ketone Bodies / Q000096:biosynthesis*; D019344:Lactic Acid / Q000378:metabolism; D061986:MCF-7 Cells; D008928:Mitochondria / Q000378:metabolism*; D063269:Mitochondrial Turnover; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
D000101:Acetyl-CoA C-Acetyltransferase; D051242:Caveolin 1; D018834:Chaperonin 60; D003373:Coumaric Acids; D007657:Ketone Bodies; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D051900:Smad3 Protein; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C007175:alpha-cyano-4-hydroxycinnamate; C506639:ACAT1 protein, human