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GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer

Acta Pharmaceutica Sinica B 2024年第2期14卷 698-711页

作者： Qiwei Jiang Yong Li Songwang Cai Xingyuan Shi Yang Yang Zihao Xing Zhenjie He Shengte Wang Yubin Su Meiwan Chen Zhesheng Chen Zhi Shi Department of Cell Biology&Institute of Biomedicine National Engineering Research Center of Genetic MedicineState Key Laboratory of Bioactive Molecules and Druggability AssessmentMOE Key Laboratory of Tumor Molecular BiologyGuangdong Provincial Key Laboratory of Bioengineering MedicineCollege of Life Science and TechnologyJinan UniversityGuangzhou 510632China Department of Gastrointestinal Surgery&General Surgery the Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou 510080China Department of Thoracic Surgery The First Affiliated Hospital of Jinan UniversityGuangzhou 510632China Department of Radiation Oncology The Fifth Hospital of Guangzhou Medical UniversityGuangzhou 510150China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 519000China Department of Pharmaceutical sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA

Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

关键词： Gastric cancer GLUL N-Cadherin β-Catenin Enzyme

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AHA1 upregulates IDH1 and metabolic activity to promote growth and metastasis and predicts prognosis in osteosarcoma

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Signal Transduction and Targeted Therapy 2021年第2期6卷 507-518页

作者： Diwei Zheng Weihai Liu Wenlin Xie Guanyu Huang Qiwei Jiang Yang Yang Jiarong Huang Zihao Xing Mengling Yuan Mengning Wei Yao Li Junqiang Yin Jingnan Shen Zhi Shi Department of Cell Biology&Institute of Biomedicine National Engineering Research Center of Genetic MedicineMOE Key Laboratory of Tumor Molecular BiologyGuangdong Provincial Key Laboratory of Bioengineering MedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouGuangdong 510632China Department of Musculoskeletal Oncology.the First Alilated Hospital of Sun Yat-sen University GuangzhouGuangdong 510080China guangdong Provincial Key Laboratory of Orthopedics and Traumatology GuangzhouGuangdong 510080China Department of Pathology the Seventh Aflited Hospital of Sun Yat-sen UniversityShenzhenGuangdong 518017China

Osteosarcoma(OS)is the most common primary malignant bone tumor in children and *** activator of HSP90 ATPase activity 1(AHA1)is reported to be a potential oncogene,its role in osteosarcoma progression remains largely *** metabolism reprogramming is involved in tumorigenesis and cancer metastasis,the relationship between AHA1 and cancer metabolism is *** this study,we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma ***1 promotes the growth and metastasis of osteosarcoma both in vitro and in ***,AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in ***,we identifed that isocitrate dehydrogenase 1(IDH1)is a novel client protein of Hsp90 ***,the IDH1 protein level was positively correlated with AHA1 in *** IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of ***,high IDH1 level was also associated with poor prognosis of osteosarcoma *** study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis,which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.

关键词： IDH1 osteosarcoma metastasis

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