Extracellular metabolic energetics can promote cancer progression Journal Article
| Authors: | Loo, J. M.; Scherl, A.; Nguyen, A.; Man, F. Y.; Weinberg, E.; Zeng, Z.; Saltz, L.; Paty, P. B.; Tavazoie, S. F. |
| Article Title: | Extracellular metabolic energetics can promote cancer progression |
| 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. © 2015 Elsevier Inc. |
| Keywords: | controlled study; unclassified drug; cancer growth; nonhuman; colorectal cancer; mouse; cell death; cell survival; cell compartmentalization; microrna; protein targeting; animal experiment; animal model; caspase 3; energy transfer; cell hypoxia; catalysis; extracellular space; tumor microenvironment; creatine phosphate; caspase 7; colorectal liver metastasis; creatine kinase bb; male; priority journal; article; microrna 483 5p; microrna 551a |
| Journal Title: | Cell |
| Volume: | 160 |
| Issue: | 3 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2015-01-29 |
| Start Page: | 393 |
| End Page: | 406 |
| Language: | English |
| DOI: | 10.1016/j.cell.2014.12.018 |
| PROVIDER: | scopus |
| PMCID: | PMC4312495 |
| PUBMED: | 25601461 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 October 2016 -- Source: Scopus |
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