OncoTargets and Therapy (Sep 2019)
OGDH promotes the progression of gastric cancer by regulating mitochondrial bioenergetics and Wnt/β-catenin signal pathway
Abstract
Xin Lu,1 Nan Wu,2 Wanli Yang,2 Jia Sun,3 Kemin Yan,3 Jing Wu1 1Biomedical-Information Engineering Laboratory of State Ministry of Education, Shaanxi Key Laboratory of Biomedical Engineering, School of Life and Science Technology, Xi’an Jiaotong University, Xi’an, Shaanxi 710049, People’s Republic of China; 2Laboratory of Tissue Engineering, Faculty of Life Science, Northwest University, Xi’an, Shaanxi 710069, People’s Republic of China; 3State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, Shaanxi 710032, People’s Republic of ChinaCorrespondence: Jing WuBiomedical-Information Engineering Laboratory of State Ministry of Education, Shaanxi Key Laboratory of Biomedical Engineering, School of Life and Science Technology, Xi’an Jiaotong University, 28 Xian Ning Western Road, Xi’an City, Shaanxi Province 710049, People’s Republic of ChinaEmail [email protected]/aims: 2-oxoglutarate dehydrogenase (OGDH) is the first rate-limiting E1 subunit of OGDH complex (OGDHC), which plays as a regulatory point in the cross-road of TCA cycle and glutamine metabolism. Until now, the role of OGDH in carcinogenesis has been unclear.Methods: In the present study, we determined the expression of OGDH in human gastric cancer (GC) tissues and cell lines by RT-qPCR, Western blotting and immunohistochemical staining respectively. The biological impacts of OGDH on cell growth and migration were explored through modulation OGDH expression in GC cells. Furthermore, mitochondrial functions and Wnt/β-catenin signal were analyzed to elucidate the mechanism by which OGDH was involved in GC progression.Results: The results showed that the levels of OGDH mRNA and protein were significantly higher in GC tissues, which was positively correlated with clinicalpathological parameters of GC patients. OGDH inhibitor SP significantly suppressed GC cell viability. Modulation of OGDH had distinct effects on cell proliferation, cell cycle and cell migration in the GC cell lines AGS and BGC823. Overexpression of OGDH resulted in the downregulation of the EMT molecular markers E-cadherin and ZO-1, the upregulation of N-cadherin and claudin-1. OGDH deficiency had the opposite outcomes in GC cells. Meantime, OGDH knockdown cells showed decreased mitochondrial membrane potential, oxygen consumption rate, intracellular ATP product, and increased ROS level and NADP+/NADPH ratio. Consistently, overexpression of OGDH enhanced the mitochondrial function in GC cells. Furthermore, OGDH knockdown reduced the expressions of β-catenin, slug and TCF8/ZEB1, and the downstream targets cyclin D1 and MMP9 in GC cells. OGDH overexpression facilitated the activation of Wnt/β-catenin signal pathway. Additionally, overexpression of OGDH promoted tumorigenesis of GC cells in nude mice.Conclusion: Taken together, these results indicate that OGDH serves as a positive regulator of GC progression through enhancement of mitochondrial function and activation of Wnt/β-catenin signaling.Keywords: 2-oxoglutarate dehydrogenase, cell proliferation, epithelial-to-mesenchymal transition, gastric cancer, mitochondrial function, Wnt/β-catenin signal
