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p53/Lactate dehydrogenase A axis negatively regulates aerobic glycolysis and tumor progression in breast cancer expressing wild-type p53

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成果类型:
期刊论文
作者:
Zhou, Yao;Niu, Weihong;Luo, Yanwei;Li, Hui;Xie, Yong;Wang, Heran;Liu, Yukun;Fan, Songqing;Li, Zheng;Xiong, Wei;Li, Xiaoling;Ren, Caiping;Tan, Ming;Li, Guiyuan;Zhou, Ming*
通讯作者:
Zhou, Ming
作者机构:
[Zhou, Yao; Zhou, Ming; Wang, Heran; Liu, Yukun; Niu, Weihong; Li, Guiyuan] Cent S Univ, Xiangya Med Sch, Affiliated Tumor Hosp, Changsha, Hunan, Peoples R China.
[Zhou, Yao; Li, Zheng; Li, Xiaoling; Luo, Yanwei; Zhou, Ming; Wang, Heran; Liu, Yukun; Xiong, Wei; Ren, Caiping; Niu, Weihong; Li, Guiyuan] Cent S Univ, Sch Basic Med Sci, Canc Res Inst, Changsha, Hunan, Peoples R China.
[Zhou, Yao; Li, Zheng; Li, Xiaoling; Luo, Yanwei; Zhou, Ming; Xiong, Wei; Niu, Weihong; Li, Guiyuan] Cent S Univ, Key Lab Carcinogenesis & Canc Invas, Chinese Minist Educ, Xiangya Hosp,Key Lab Carcinogenesis,Chinese Minis, Changsha, Hunan, Peoples R China.
[Li, Hui; Fan, Songqing; Xie, Yong] Cent S Univ, Xiang Ya Hosp 2, Changsha, Hunan, Peoples R China.
[Li, Zheng] Cent S Univ, Adv Res Ctr, High Resolut Mass Spectrometry Lab, Changsha, Hunan, Peoples R China.
通讯机构:
[Zhou, Ming] Cent S Univ, Xiangya Med Sch, Affiliated Tumor Hosp, Changsha, Hunan, Peoples R China.
语种:
英文
关键词:
aerobic glycolysis;breast cancer;lactate dehydrogenase A;p53;tumor progression
期刊:
CANCER SCIENCE
ISSN:
1347-9032
年:
2019
卷:
110
期:
3
页码:
939-949
文献类别:
WOS:Article
所属学科:
WOS学科类别:Oncology
入藏号:
基金类别:
National Natural Science Foundation of China [81572748]; Free Exploration Program of Central South University [2018zzts233, 2018zzts823]; Fundamental Research Funds for the Central Universities of Central South University [2016zzts114]; "111" project [111-2-12]
机构署名:
本校为第一且通讯机构
院系归属:
基础医学院
湘雅医院(第一临床学院)
湘雅二医院(第二临床学院)
摘要:
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.
参考文献:
Allison SJ, 2014, ONCOGENESIS, V3, DOI 10.1038/oncsis.2014.16
Anastasiou D, 2012, NAT CHEM BIOL, V8, P839, DOI 10.1038/NCHEMBIO.1060
Cadwell C, 2001, GENE, V277, P15, DOI 10.1016/S0378-1119(01)00696-5
CHUNG FZ, 1985, BIOCHEM J, V231, P537, DOI 10.1042/bj2310537
Cui JJ, 2014, CLIN CANCER RES, V20, P2595, DOI 10.1158/1078-0432.CCR-13-2407

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