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Cell. 2015 Jan 29;160(3):393-406. doi: 10.1016/j.cell.2014.12.018. Epub 2015 Jan 15.

Extracellular metabolic energetics can promote cancer progression.

Author information

1
Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
2
Department of Surgery, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Medicine, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA. Electronic address: stavazoie@mail.rockefeller.edu.

Abstract

Colorectal cancer primarily metastasizes to the liver and globally kills over 600,000 people annually. By functionally screening 661 microRNAs (miRNAs) in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP—fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastasis, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting.

PMID:
25601461
PMCID:
PMC4312495
DOI:
10.1016/j.cell.2014.12.018
[Indexed for MEDLINE]
Free PMC Article
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