p53/Lactate dehydrogenase A axis negatively regulates aerobic glycolysis and tumor progression in breast cancer expressing wild-type p53
p53/Lactate dehydrogenase A axis negatively regulates aerobic glycolysis and tumor progression in breast cancer expressing wild-type p53
复制标题
p53/LDHA 轴负向调节表达野生型 p53 的乳腺癌的有氧糖酵解和肿瘤进展
DOI：
10.1111/cas.13928
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发表时间：
2019-03-01
期刊：
影响因子：
5.7
通讯作者：
Zhou, Ming
中科院分区：
文献类型：
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作者：
Zhou, Yao;Niu, Weihong;Zhou, Ming
肿瘤抑制因子p53是细胞凋亡的主要调节因子，在细胞周期检查点中起关键作用。p53通过癌症中的几种机制响应代谢变化并改变代谢。乳酸脱氢酶A（LDHA）是糖酵解的关键酶，在多种肿瘤中高度表达，催化丙酮酸转化为乳酸。在本研究中，我们首先分析了p53和LDHA在表达野生型p53（wt-p53）的乳腺癌中的相关性和临床意义，发现LDHA mRNA水平与wt-p53呈负相关，但与突变型p53 mRNA水平无关，低p53和高LDHA表达与总生存率低显著相关。此外，p53通过直接结合其启动子区域负调控LDHA表达。此外，在表达内源性wt-p53的乳腺癌MCF 7细胞中进行了一系列LDHA功能获得和再评分实验，表明p53的异位表达降低了有氧糖酵解、细胞增殖、迁移，乳腺癌细胞侵袭和肿瘤形成以及p53-过表达细胞可消除p53对有氧糖酵解和其它恶性表型的抑制作用。总之，我们的研究结果表明，抑制LDHA诱导的wt-p53阻断肿瘤的生长和侵袭，通过下调有氧糖酵解在乳腺癌中，提供了新的见解的机制，p53有助于乳腺癌的发展和进展。
Tumor suppressor p53 is a master regulator of apoptosis and plays key roles in cell cycle checkpoints. p53 responds to metabolic changes and alters metabolism through several mechanisms in cancer. Lactate dehydrogenase A (LDHA), a key enzyme in glycolysis, is highly expressed in a variety of tumors and catalyzes pyruvate to lactate. In the present study, we first analyzed the association and clinical significance of p53 and LDHA in breast cancer expressing wild-type p53 (wt-p53) and found that LDHA mRNA levels are negatively correlated with wt-p53 but not with mutation p53 mRNA levels, and low p53 and high LDHA expression are significantly associated with poor overall survival rates. Furthermore, p53 negatively regulates LDHA expression by directly binding its promoter region. Moreover, a series of LDHA gain-of-function and rescore experiments were carried out in breast cancer MCF7 cells expressing endogenous wt-p53, showing that ectopic expression of p53 decreases aerobic glycolysis, cell proliferation, migration, invasion and tumor formation of breast cancer cells and that restoration of the expression of LDHA in p53-overexpressing cells could abolish the suppressive effect of p53 on aerobic glycolysis and other malignant phenotypes. In conclusion, our findings showed that repression of LDHA induced by wt-p53 blocks tumor growth and invasion through downregulation of aerobic glycolysis in breast cancer, providing new insights into the mechanism by which p53 contributes to the development and progression of breast cancer.