Abstract
TRAF6 has been reported to be associated with poor prognosis in non-small-cell lung cancer (NSCLC). However, its precise role in tumor development has not been elaborated. In the present study, the function and the mechanism by which TRAF6 contributes to development were intensively investigated. TRAF6 was found to be overexpressed in primary NSCLC tumor tissue and all tested cell lines. Knockdown of TRAF6 with shRNA substantially attenuated NSCLC cell proliferation and anchorage-independent growth. Moreover, tumor glycolysis, such as glucose consumption and lactate production, also significantly impaired. In TRAF6-deficient cells, hexokinase-2 expression was significantly reduced, which was caused by the decrease of HIF-1α transcriptional activity. Further investigations demonstrated that TRAF6 played an important role in the regulation of Akt activation, and exogenous overexpression of constitutively activated Akt substantially rescued glycolysis suppression in TRAF6 knockdown cells. The results of the xenograft model confirmed that downregulation of TRAF6 in NSCLC tumor cells dramatically restrained tumor growth in vivo. Taken together, our studies revealed the mechanism by which TRAF6 exerts its role in NSCLC development and suggested TRAF6 maybe was a promising candidate target for lung cancer prevention and therapy.
Highlights
When oxygen is available, the energy supply in normal cells is powered by the oxidative phosphorylation systems (OXPHOS) in mitochondria
With no use of OXPHOS, glycolysis is utilized by tumor cells to consume more glucose and produce large amounts of lactic acid, even in the presence of oxygen, a phenomenon known as aerobic glycolysis, or the Warburg effect [1]
TRAF6 Is Overexpressed in non-small-cell lung cancer (NSCLC) and Important for Tumor Cell Proliferation
Summary
The energy supply in normal cells is powered by the oxidative phosphorylation systems (OXPHOS) in mitochondria. With no use of OXPHOS, glycolysis is utilized by tumor cells to consume more glucose and produce large amounts of lactic acid, even in the presence of oxygen, a phenomenon known as aerobic glycolysis, or the Warburg effect [1]. Owing to the rapid growth, tumor cells are in a state of long-term hypoxia. The active glycolysis can strengthen the tolerance to hypoxia, avoiding cell apoptosis induced by OXPHOS inhibition. The lactate produced by tumor glycolysis creates an acidic environment, which can break down the extracellular matrix and facilitate the invasion and migration of cancer cells [4]. Recent studies have shown that lactate can regulate the function of dendritic cells in the tumor microenvironment and affect the immune responses [5, 6]
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