Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells | Health & Environmental Research Online (HERO)

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Citation
Tags

HERO ID

1454552

Reference Type

Journal Article

Title

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

Author(s)

Martinez-Outschoorn, UE; Lin, Z; Whitaker-Menezes, D; Howell, A; Lisanti, MP; Sotgia, F

Year

2012

Is Peer Reviewed?

Yes

Journal

Cell Cycle
ISSN: 1538-4101
EISSN: 1551-4005

Volume

Issue

Page Numbers

3956-3963

Language

English

PMID

23082721

DOI

10.4161/cc.22136

Web of Science Id

WOS:000310583500016

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.

Keywords

ketone body; 3-hydroxy-butyrate; cancer metabolism; BDH1; HMGCS2; ACAT isoforms; tumor growth; metastasis