Ketone body utilization drives tumor growth and metastasis

We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm "two-compartment tumor metabolism." Here, we further tested...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Cell cycle (Georgetown, Tex.) Ročník 11; číslo 21; s. 3964 - 3971
Hlavní autoři:	Martinez-Outschoorn, Ubaldo E., Lin, Zhao, Whitaker-Menezes, Diana, Howell, Anthony, Sotgia, Federica, Lisanti, Michael P.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Taylor & Francis 01.11.2012 Landes Bioscience
Témata:	3-hydroxy-butyrate ACAT isoforms Acetyl-CoA C-Acetyltransferase - metabolism Animals Autophagy BDH1 Binding Biology Bioscience Breast Neoplasms - blood supply Breast Neoplasms - metabolism Breast Neoplasms - pathology Calcium Cancer cancer metabolism Caveolin 1 - genetics Caveolin 1 - metabolism Cell Cell Line Cell Movement Cell Proliferation Coculture Techniques Coenzyme A-Transferases - metabolism Cycle Female HMGCS2 Humans Hydroxymethylglutaryl-CoA Synthase - metabolism Ketone Bodies - metabolism ketone body Landes MCF-7 Cells metastasis Mice Mice, Nude Mitochondrial Turnover Neovascularization, Pathologic Organogenesis OXCT isoforms Proteins Sterol O-Acyltransferase - metabolism Sterol O-Acyltransferase 2 Transplantation, Heterologous tumor growth
ISSN:	1538-4101, 1551-4005, 1551-4005
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm "two-compartment tumor metabolism." Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current affiliation: University of Manchester; Breakthrough Breast Cancer Research Unit; Manchester, UK
ISSN:	1538-4101 1551-4005 1551-4005
DOI:	10.4161/cc.22137