Intracellular citrate accumulation by oxidized ATM-mediated metabolism reprogramming via PFKP and CS enhances hypoxic breast cancer cell invasion and metastasis

Meixi Peng; Dan Yang; Yixuan Hou; Shuiqing Liu; Maojia Zhao; Yilu Qin; Rui Chen; Yong Teng; Manran Liu

doi:10.1038/s41419-019-1475-7

Intracellular citrate accumulation by oxidized ATM-mediated metabolism reprogramming via PFKP and CS enhances hypoxic breast cancer cell invasion and metastasis

Cell Death Dis. 2019 Mar 8;10(3):228. doi: 10.1038/s41419-019-1475-7.

Authors

Meixi Peng¹, Dan Yang¹, Yixuan Hou^{1

2}, Shuiqing Liu¹, Maojia Zhao¹, Yilu Qin¹, Rui Chen³, Yong Teng⁴, Manran Liu⁵

Affiliations

¹ Key Laboratory of Laboratory Medical Diagnostics Designed by Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
² Experimental Teaching Center of Basic Medicine Science, Chongqing Medical University, Chongqing, 400016, China.
³ Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
⁴ Georgia Cancer Center, Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.
⁵ Key Laboratory of Laboratory Medical Diagnostics Designed by Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China. [email protected].

Abstract

Citrate, a substance being related to de novo fatty acid synthesis and tricarboxylic acid (TCA) cycle, has a pivotal role in cell survival. However, the molecular mechanisms that regulate intracellular citrate in triple-negative breast cancer (TNBC), especially under hypoxic condition, remain poorly understood. Here we find that hypoxia (1% O₂) induces DNA damage-independent ATM activation (oxidized ATM) and suppression of oxidized ATM reduces intracellular citrate via decreasing the levels of phosphofructokinase (PFKP) and citrate synthase (CS), two key glucose metabolism-associated enzymes. Mechanistically, PFKP is regulated by HIF1A at the translational level, whereas CS is of posttranscriptional regulation by UBR5-mediated ubiquitination. Interestingly, accumulation of citrate in cytoplasm or exogenous citrate significantly enhances cell migration, invasion, and metastasis of hypoxic TNBC cells in vitro and in mice xenografts. The underlying mechanism mainly involves citrate-stimulated activation of the AKT/ERK/MMP2/9 signaling axis. Our findings unravel a novel function of oxidized ATM in promoting migration, invasion, and metastasis of TNBC.

Publication types

Research Support, Non-U.S. Gov't
Retracted Publication

MeSH terms

Animals
Ataxia Telangiectasia Mutated Proteins / chemistry
Ataxia Telangiectasia Mutated Proteins / genetics
Ataxia Telangiectasia Mutated Proteins / metabolism*
Cell Hypoxia
Cell Line, Tumor
Cell Movement / genetics
Cell Respiration
Cell Survival / genetics
Citrate (si)-Synthase / genetics
Citrate (si)-Synthase / metabolism*
Citric Acid / metabolism*
Energy Metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Matrix Metalloproteinase 2 / genetics
Matrix Metalloproteinase 2 / metabolism
Mice
Mice, Nude
Neoplasm Metastasis
Phosphofructokinase-1 / genetics
Phosphofructokinase-1 / metabolism*
Signal Transduction / genetics
Transplantation, Heterologous
Triple Negative Breast Neoplasms / enzymology
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / metabolism*
Triple Negative Breast Neoplasms / pathology
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Citric Acid
UBR5 protein, human
Ubiquitin-Protein Ligases
Citrate (si)-Synthase
Phosphofructokinase-1
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
MMP2 protein, human
Matrix Metalloproteinase 2