SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation.
SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation.
复制标题
DOI：
10.1038/cddis.2014.482
复制
发表时间：
2014-11-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
细胞代谢重新编程以从头产生丝氨酸，促进癌细胞的生长，提供氨基酸和核苷酸等必需前体，并控制细胞的抗氧化和甲基化能力。丝氨酸羟甲基转移酶 (SHMT) 在这种代谢转变中起着关键作用，并将丝氨酸碳引导至一碳单位代谢和胸苷酸合成。虽然 SHMT 线粒体同工型 (SHMT2) 最近被确定为控制多种癌症类型中细胞增殖的重要参与者，并且是抗癌治疗的热门靶标，但细胞质同工型 (SHMT1) 在癌症发生中的作用目前尚不清楚。在本文中，我们表明 SHMT1 在肺癌患者和肺癌细胞系的组织样本中过度表达，这表明在这种广泛存在的肿瘤类型中，SHMT1 发挥着相关作用。我们发现肺癌细胞中 SHMT1 敲低会导致细胞周期停滞，更重要的是，导致 p53 依赖性细胞凋亡。我们的数据表明，细胞凋亡的诱导并不依赖于丝氨酸或甘氨酸饥饿，而是由于DNA复制过程中尿嘧啶积累的增加。
Reprogramming of cellular metabolism towards de novo serine production fuels the growth of cancer cells, providing essential precursors such as amino acids and nucleotides and controlling the antioxidant and methylation capacities of the cell. The enzyme serine hydroxymethyltransferase (SHMT) has a key role in this metabolic shift, and directs serine carbons to one-carbon units metabolism and thymidilate synthesis. While the mitochondrial isoform of SHMT (SHMT2) has recently been identified as an important player in the control of cell proliferation in several cancer types and as a hot target for anticancer therapies, the role of the cytoplasmic isoform (SHMT1) in cancerogenesis is currently less defined. In this paper we show that SHMT1 is overexpressed in tissue samples from lung cancer patients and lung cancer cell lines, suggesting that, in this widespread type of tumor, SHMT1 plays a relevant role. We show that SHMT1 knockdown in lung cancer cells leads to cell cycle arrest and, more importantly, to p53-dependent apoptosis. Our data demonstrate that the induction of apoptosis does not depend on serine or glycine starvation, but is because of the increased uracil accumulation during DNA replication.
登录
查看更多内容
影响因子：
4.8
作者：
Stover, PJ;Chen, LH;Shane, B
通讯作者：
Shane, B
影响因子：
4.8
作者：
Duthie, SJ;Hawdon, A
通讯作者：
Hawdon, A
影响因子：
64.8
作者：
Possemato, Richard;Marks, Kevin M.;Shaul, Yoav D.;Pacold, Michael E.;Kim, Dohoon;Birsoy, Kivanc;Sethumadhavan, Shalini;Woo, Hin-Koon;Jang, Hyun G.;Jha, Abhishek K.;Chen, Walter W.;Barrett, Francesca G.;Stransky, Nicolas;Tsun, Zhi-Yang;Cowley, Glenn S.;Barretina, Jordi;Kalaany, Nada Y.;Hsu, Peggy P.;Ottina, Kathleen;Chan, Albert M.;Yuan, Bingbing;Garraway, Levi A.;Root, David E.;Mino-Kenudson, Mari;Brachtel, Elena F.;Driggers, Edward M.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
4.8
作者：
Lin, DL;Chang, CS
通讯作者：
Chang, CS
影响因子：
64.5
作者：
Zhang, Wen Cai;Shyh-Chang, Ng;Lim, Bing
通讯作者：
Lim, Bing