Extracellular metabolic energetics can promote cancer progression.
Extracellular metabolic energetics can promote cancer progression.
复制标题
细胞外代谢能量可以促进癌症的进展。
DOI：
10.1016/j.cell.2014.12.018
复制
发表时间：
2015-01-29
期刊：
影响因子：
64.5
通讯作者：
Tavazoie SF
中科院分区：
文献类型：
--
作者：
Loo JM;Scherl A;Nguyen A;Man FY;Weinberg E;Zeng Z;Saltz L;Paty PB;Tavazoie SF
结直肠癌主要转移到肝脏，每年导致60多万人死亡。通过在肝脏定植过程中对661个miRNAs进行功能筛选，我们发现miR-551a和miR-483是肝脏定植和转移的内源性抑制因子。这些miRNAs集中靶向肌酸激酶，脑型(CKB)，它使代谢产物肌酸磷酸化，产生磷酸肌酸。CKB由遇到肝脏缺氧的转移细胞释放到细胞外空间，并催化细胞外磷酸肌酸的产生，后者通过SLC6A8转运体输入，用于产生ATP燃料的转移生存。通过单剂量腺相关病毒(AAV)传递miR-551a和miR-483-5p的联合治疗性病毒显著抑制结肠癌的转移定植，小分子抑制剂对CKB的抑制也是如此。重要的是，与原发肿瘤相比，人肝转移瘤表达更高的CKB和SLC6A8水平，而降低miR-551a/miR-483水平。我们认为细胞外空间是恶性能量催化和治疗靶向的重要隔间。
Colorectal cancer primarily metastasizes to the liver and kills over 600,000 people annually. By functionally screening 661 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 extracellular 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 metastatic colonization, 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.
登录
查看更多内容
DOI：
10.1038/newbio242148a0
发表时间：
1973-01-01
期刊：
NATURE-NEW BIOLOGY
影响因子：
--
作者：
FIDLER, IJ
通讯作者：
FIDLER, IJ
影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.7
作者：
Huddleston, HG;Wong, KK;Mok, SC
通讯作者：
Mok, SC
影响因子：
50.3
作者：
Kang, YB;Siegel, PM;Massagué, J
通讯作者：
Massagué, J