Zhang Jun, Wang Yanzhong, Li Guiling, Yu Haitao, Xie Xinyou
Clinical Laboratory, Sir RunRun Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Clinical Laboratory, Sir RunRun Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China ; Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
PLoS One. 2014 Feb 18;9(2):e89202. doi: 10.1371/journal.pone.0089202. eCollection 2014.
Nicotinamide N-methyltransferase (NNMT) has been found involved in cell proliferation of several malignancies. However, the functional role of NNMT in breast cancer has not been elucidated. In the present study, we showed that NNMT was selectively expressed in some breast cancer cell lines, down-regulation of NNMT expression in Bcap-37 and MDA-MB-231 cell lines by NNMT shRNA significantly inhibited cell growth in vitro, decreased tumorigenicity in mice and induced apoptosis. The silencing reciprocal effect of NNMT was confirmed by over-expressing NNMT in the MCF-7 and SK-BR-3 breast cancer cell lines which lack constitutive expression of NNMT. In addition, down-regulation of NNMT expression resulted in reducing expression of Bcl-2 and Bcl-xL, up-regulation of Bax, Puma, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, increasing reactive oxygen species production and release of cytochrome c from mitochondria, and decreasing the phosphorylation of Akt and ERK1/2. These data suggest that down-regulation of NNMT induces apoptosis via the mitochondria-mediated pathway in breast cancer cells.
烟酰胺N-甲基转移酶（NNMT）已被发现参与多种恶性肿瘤的细胞增殖过程。然而，NNMT在乳腺癌中的功能作用尚未阐明。在本研究中，我们发现NNMT在某些乳腺癌细胞系中选择性表达，通过NNMT短发夹RNA（shRNA）下调Bcap-37和MDA-MB-231细胞系中的NNMT表达，显著抑制了体外细胞生长，降低了小鼠体内的致瘤性并诱导了细胞凋亡。在缺乏NNMT组成型表达的MCF-7和SK-BR-3乳腺癌细胞系中过表达NNMT，证实了NNMT的沉默反向效应。此外，下调NNMT表达导致Bcl-2和Bcl-xL表达降低，Bax、Puma、裂解的caspase-9、裂解的caspase-3和裂解的PARP表达上调，活性氧生成增加以及细胞色素c从线粒体释放，同时降低Akt和ERK1/2的磷酸化水平。这些数据表明，下调NNMT可通过线粒体介导的途径诱导乳腺癌细胞凋亡。
