RATE OF HYDRATION OF ALITE AND BELITE IN PORTLAND CEMENT

Abstract

Graphical Abstract Highlights d miR-551a and miR-483-5p suppress colon cancer metastasis by targeting CKB d CKB promote metastatic survival by modulating intra-and extracellular energetics d miRNAs and CKB can be therapeutically targeted by AAV and small molecule delivery In Brief The tumor microenvironment is a rich source of metabolic substrates that could be utilized by cancer cells. Colon cancer cells secrete a kinase that acts extracellularly to generate one such metabolite, phosphocreatinine, that directly fuels tumor growth and metastasis to the liver. Accession Numbers GSE56320 Loo et al., 2015, Cell 160, 393–406 January 29, 2015 ª2015 Elsevier Inc. SUMMARY 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 identi-fied 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 metabo-lite 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. Combi-natorial 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 pri-mary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting.