Zhao Jiangsha, Li Jieran, Fan Teresa W M, Hou Steven X
The Basic Research Laboratory, National Cancer Institute, National Institutes of Health Frederick, Frederick, MD 21702, USA.
Graduate Center of Toxicology and Cancer Biology, Center for Environmental and Systems Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Oncotarget. 2017 Jun 28;8(48):83602-83618. doi: 10.18632/oncotarget.18787. eCollection 2017 Oct 13.
Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein acetylation. Our data suggest PCK2 promotes tumor initiation by lowering acetyl-CoA level through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate tumors.
肿瘤起始细胞（TICs）在肿瘤进展和转移中发挥着重要作用。识别调控TICs的因素可能为癌症治疗开辟新途径。在此，我们表明，与低TICs的克隆相比，富含TICs的前列腺癌细胞克隆消耗更多葡萄糖并分泌更多乳酸。我们确定，磷酸烯醇丙酮酸羧激酶同工酶2（PCK2）水平升高对于前列腺癌中TICs的代谢转换和维持至关重要。来自前列腺癌患者数据库的信息显示，较高的PCK2水平与更具侵袭性的肿瘤和较低的生存率相关。PCK2基因敲低导致TIC数量减少、胞质乙酰辅酶A增加和细胞蛋白乙酰化。我们的数据表明，PCK2通过减少线粒体三羧酸（TCA）循环来降低乙酰辅酶A水平，从而促进肿瘤起始。因此，PCK2是侵袭性前列腺肿瘤的一个潜在治疗靶点。
