TRIB3 Promotes Lung Adenocarcinoma Progression via an Enhanced Warburg Effect

Yutong Xing,1,2,* Peng Luo,2,* Rui Hu,1 Duanduan Wang,1 Gang Zhou,2 Jie Jiang3 1Department of Cardiothoracic Surgery, The Fifth Hospital of Xiamen, Xiamen, People’s Republic of China; 2Department of Cardiothoracic Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, People’s Republic of China; 3Department of Thoracic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yutong Xing Department of Cardiothoracic SurgeryThe Fifth Hospital of Xiamen, Xiamen, Fujian 361101, People’s Republic of ChinaEmail xingyt2018@163.comBackground: The pseudokinase Tribbles 3 (TRIB3) is involved in many cellular processes and various cancers. In recent years, the importance of metabolic transformation in the maintenance of malignant tumors has become increasingly prominent. Abnormal metabolism of cancer cells is considered a hallmark of cancer. However, the exact role and molecular mechanism of TRIB3 in lung adenocarcinoma (LUAD) cell reprogramming is largely unknown.Methods: The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of cells were examined with a Seahorse XF Extracellular Flux Analyzer. In vitro and in vivo RT-qPCR, Western blotting, and functional assays were performed to explore the functional roles of TRIB3 in LUAD.Results: In the present study, we demonstrated that TRIB3 is remarkably upregulated in LUAD cell lines as well as tissues. TRIB3 knockdown significantly inhibited LUAD cell growth and suppressed LUAD cell invasion, while TRIB3 overexpression conferred the opposite effects. Moreover, silencing TRIB3 suppressed the tumorigenesis and metastatic ability of LUAD cells. Mechanistically, we demonstrated that silencing TRIB3 significantly impaired aerobic glycolysis ability in LUAD cells. Furthermore, our data indicated that TRIB3 knockdown decreased hypoxia-inducible factor (HIF)1α levels and targeted the glycolytic genes regulated by HIF1α.Conclusion: Together, our findings revealed a previously unappreciated function of TRIB3 in cancer cell metabolism and tumor progression, illustrating that TRIB3 could be considered a valuable therapeutic target for LUAD patients.Keywords: TRIB3, LUAD, aerobic glycolysis, HIF1&alpha