Secreted creatine kinase brain (CKB) promotes liver colonization and colon cancer metastasis.
Major finding: Secreted creatine kinase brain (CKB) promotes liver colonization and colon cancer metastasis.
Mechanism: Extracellular CKB generates phosphocreatine, which is imported via SLC6A8 for ATP production.
Impact: Therapeutics targeting CKB may prove effective against colorectal cancer metastases.
Metastatic colonization of the liver is a primary cause of death in patients with colorectal cancer. The liver is a major organ for miRNA accumulation and has been shown to respond to adeno-associated viruses and nanoparticle delivery vectors, prompting Loo and colleagues to search for miRNAs that suppress colorectal cancer metastasis to the liver. A functional screen of 661 miRNAs identified miR-551a and miR-483-5p as endogenous suppressors of metastatic liver colonization in vivo. Depletion of either miRNA enhanced the ability of metastatic colorectal cancer cells to survive in the liver microenvironment in vitro and in vivo. Both miR-551a and miR-483-5p negatively regulated expression of creatine kinase brain (CKB). Overexpression of CKB resulted in increased liver metastasis in vivo, whereas depletion of CKB in metastatic cells inhibited liver colonization. CKB levels directly paralleled intracellular phosphocreatine and ATP levels, implicating miRNA-mediated regulation of CKB in the control of energy availability in metastatic colorectal cancer cells. CKB was secreted by disseminated colorectal cancer cells in the liver and catalyzed the conversion of extracellular ATP and hepatically produced creatine into phosphocreatine, which was then imported into metastatic cancer cells via the solute carrier family 6, member 8 (SLC6A8) transport protein to provide metastatic cells with an abundant source of ATP and protect against the hypoxic liver microenvironment. Importantly, expression of both miR-551a and miR-483-5p was significantly reduced in human liver metastases compared with primary colon cancers, whereas CKB and SLC6A8 expression was significantly enhanced in metastatic liver samples. Furthermore, therapeutic treatment of mice bearing incipient hepatic metastases with adeno-associated virus encoding miR-551a and miR-483-5p significantly reduced metastatic colonization, similar to the effect of treatment with the small-molecule CKB inhibitor cyclocreatine. Overall, these findings demonstrate the role of extracellular metabolism in metastatic progression, and suggest that targeted inhibition of this pathway may provide clinical benefit in advanced colorectal cancer.