Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells.

Abstract

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.

• Authors: Ubaldo E Martinez-Outschoorn, Zhao Lin, Diana Whitaker-Menezes, Anthony Howell, Michael P Lisanti, Federica Sotgia
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 11 Issue 21 Pg. 3956-63 (Nov 01 2012) ISSN: 1551-4005 [Electronic] United States
• PMID: 23082721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caveolin 1
• Chaperonin 60
• Coumaric Acids
• Ketone Bodies
• Monocarboxylic Acid Transporters
• RNA, Small Interfering
• Smad2 Protein
• Smad3 Protein
• Symporters
• monocarboxylate transport protein 1
• alpha-cyano-4-hydroxycinnamate
• Lactic Acid
• ACAT1 protein, human
• Acetyl-CoA C-Acetyltransferase

Topics

• Acetyl-CoA C-Acetyltransferase (metabolism)
• Breast Neoplasms (metabolism, pathology)
• Caveolin 1 (antagonists & inhibitors, genetics, metabolism)
• Cell Line
• Chaperonin 60 (metabolism)
• Coculture Techniques
• Coumaric Acids (pharmacology)
• Down-Regulation (drug effects)
• Epithelial Cells (metabolism)
• Female
• Humans
• Ketone Bodies (biosynthesis)
• Lactic Acid (metabolism)
• MCF-7 Cells
• Mitochondria (metabolism)
• Mitochondrial Turnover
• Monocarboxylic Acid Transporters (antagonists & inhibitors, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Symporters (antagonists & inhibitors, metabolism)