Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression

Cell Communication and Signaling

Tao Song¹  Jia Wang²  Feng Jin³  Yuemei Xu⁴  Yipin Wang⁵  Dongming Su⁵  Ya Fan⁵  Xiubin Liang⁶ 

[1]Center of Pathology and Clinical Laboratory, Sir Run Run Hospital of Nanjing Medical University

[2]Department of Breast Surgery, Institute of Breast Disease, The Second Hospital of Dalian Medical University

[3]Department of Breast Surgery, The First Affiliated Hospital of China Medical University

[4]Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School

[5]Department of Pathology, Nanjing Medical University

[6]Department of Pathophysiology, Nanjing Medical University

关键词: Anti-warburg effect;    Cancer progression;    Molecular patterns;    Treatment target;   

DOI  :  10.1186/s12964-020-00679-7

来源: DOAJ

【 摘 要 】

Abstract Background Our previous studies have shown that the E3 ubiquitin ligase of HMG-CoA reductase degradation 1 (HRD1) functions as a tumor suppressor, as overexpression of HRD1 suppressed breast cancer proliferation and invasion. However, its role in breast cancer cell glucose metabolism was unclear. Here, our aim was to uncover the role and molecular mechanisms of HRD1 in regulating aerobic glycolysis in breast cancer. Methods The effect of HRD1 on robic glycolysis in breast cancer cells were assessed. Then the proliferation, colony formation ability, invasion and migration of breast cancer cells were evaluated. The relationship between HRD1 and PFKP was validated by Mass spectrometry analysis, immunofluorescence and co-immunoprecipitation. The level of PFKP ubiquitination was measured using ubiquitylation assay. Furthermore, the tumor growth and metastasis in mice xenografts were observed. Results We found that upregulation of HRD1 clearly decreased aerobic glycolysis, and subsequently inhibited breast cancer proliferation and invasion. Mass spectrometry analysis results revealed a large HRD1 interactome, which included PFKP (platelet isoform of phosphofructokinase), a critical enzyme involved in the Warburg Effect in breast cancer. Mechanistically, HRD1 interacted and colocalized with PFKP in the cytoplasm, targeted PFKP for ubiquitination and degradation, and ultimately reduced PFKP expression and activity in breast cancer cells. HRD1 inhibited breast cancer growth and metastasis in vivo through a PFKP-dependent way Conclusions Our findings reveal a new regulatory role of HRD1 in Warburg effect and provide a key contributor in breast cancer metabolism. Video abstract Graphic abstract

【 授权许可】

Unknown