Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; The Southern California Research Center for Alcoholic and Pancreatic Diseases & Cirrhosis, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
Exp Cell Res. 2013 Jul 15;319(12):1902-1911. doi: 10.1016/j.yexcr.2013.04.005. Epub 2013 Apr 12.
Methionine adenosyltransferase (MAT) is an essential enzyme that is responsible for the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines. MAT1A is expressed in normal liver and MAT2A is expressed in all extrahepatic tissues. MAT2A expression is increased in human colon cancer and in colon cancer cells treated with mitogens, whereas silencing MAT2A resulted in apoptosis. The aim of the current work was to examine the mechanism responsible for MAT2A-dependent growth and apoptosis. We found that in RKO (human adenocarcinoma cell line) cells, MAT2A siRNA treatment lowered cellular SAMe and putrescine levels by 70-75%, increased apoptosis and inhibited growth. Putrescine supplementation blunted significantly MAT2A siRNA-induced apoptosis and growth suppression. Putrescine treatment (100pmol/L) raised MAT2A mRNA level to 4.3-fold of control, increased the expression of c-Jun and c-Fos and binding to an AP-1 site in the human MAT2A promoter and the promoter activity. In human colon cancer specimens, the expression levels of MAT2A, ornithine decarboxylase (ODC), c-Jun and c-Fos are all elevated as compared to adjacent non-tumorous tissues. Overexpression of ODC in RKO cells also raised MAT2A mRNA level and MAT2A promoter activity. ODC and MAT2A are also overexpressed in liver cancer and consistently, similar MAT2A-ODC-putrescine interactions and effects on growth and apoptosis were observed in HepG2 cells. In conclusion, there is a crosstalk between polyamines and MAT2A. Increased MAT2A expression provides more SAMe for polyamines biosynthesis; increased polyamine (putrescine in this case) can activate MAT2A at the transcriptional level. This along with increased ODC expression in cancer all feed forward to further enhance the proliferative capacity of the cancer cell.
蛋氨酸腺苷转移酶（MAT）是一种必需的酶，负责合成 S-腺苷甲硫氨酸（SAMe），SAMe 是主要的甲基供体和多胺的前体。MAT1A 在正常肝脏中表达，MAT2A 在所有肝外组织中表达。MAT2A 在人结肠癌和用有丝分裂原处理的结肠癌细胞中表达增加，而沉默 MAT2A 导致细胞凋亡。本研究的目的是探讨与 MAT2A 相关的生长和凋亡的机制。我们发现，在 RKO（人腺癌细胞系）细胞中，MAT2A siRNA 处理使细胞内 SAMe 和腐胺水平降低了 70-75%，增加了细胞凋亡并抑制了细胞生长。腐胺补充显著减弱了 MAT2A siRNA 诱导的细胞凋亡和生长抑制。腐胺处理（100pmol/L）使 MAT2A mRNA 水平提高到对照的 4.3 倍，增加了 c-Jun 和 c-Fos 的表达，并与人类 MAT2A 启动子和启动子活性中的 AP-1 位点结合。在人结肠癌标本中，与相邻非肿瘤组织相比，MAT2A、鸟氨酸脱羧酶（ODC）、c-Jun 和 c-Fos 的表达水平均升高。RKO 细胞中 ODC 的过表达也提高了 MAT2A mRNA 水平和 MAT2A 启动子活性。肝癌中 ODC 和 MAT2A 也过表达，并且在 HepG2 细胞中观察到类似的 MAT2A-ODC-腐胺相互作用和对生长和凋亡的影响。总之，多胺和 MAT2A 之间存在串扰。MAT2A 表达增加为多胺生物合成提供更多的 SAMe；增加的多胺（在这种情况下为腐胺）可以在转录水平上激活 MAT2A。这与癌症中 ODC 表达的增加一起，进一步增强了癌细胞的增殖能力。
