Abstract
Current studies on tumor progression focus on the roles of cytokines in the tumor microenvironment (TME), and recent research shows that transforming growth factor-β1 (TGF-β1) released from TME plays a pivotal role in tumor development and malignant transformation. The alteration in cellular metabolism is a hallmark of cancer, which not only provides cancer cells with ATP for fuel cellular reactions, but also generates metabolic intermediates for the synthesis of essential cellular ingredients, to support cell proliferation, migration, and invasion. Interestingly, we found a distinct metabolic change during TGF-β1-induced epithelial-mesenchymal transition (EMT) in glioblastoma cells. Indeed, TGF-β1 participates in metabolic reprogramming, and the molecular basis is still not well understood. NADPH oxidases 4 (NOX4), a member of the Nox family, also plays a key role in the biological effects of glioblastoma. However, the relationship between NOX4, TGF-β1, and cellular metabolic changes during EMT in glioblastoma remains obscure. Here, our findings demonstrated that TGF-β1 upregulated NOX4 expression accompanied by reactive oxygen species (ROS) through Smad-dependent signaling and then induced hypoxia-inducible factor 1α (HIF-1α) overexpression and nuclear accumulation resulting in metabolic reprogramming and promoting EMT. Besides, inhibition of glycolysis reversed EMT suggesting a causal relationship between TGF-β1-induced metabolic changes and tumorigenesis. Moreover, TGF-β1-induced metabolic reprogramming and EMT which modulated by NOX4/ROS were blocked when the phosphoinositide3-kinase (PI3K)/AKT/HIF-1α signaling pathways were inhibited. In conclusion, these suggest that NOX4/ROS induction by TGF-β1 can be one of the main mechanisms mediating the metabolic reprogramming during EMT of glioblastoma cells and provide promising strategies for cancer therapy.
Highlights
Glioblastoma multiforme (GBM) is the most prevalent primary malignant tumors affecting the human brain with a median survival of 15 months [1]
By applying qPCR (Figure 1(b)), western blot (Figure 1(c), Fig. S1(a)), and immunochemistry (Figure 1(d)) on samples with different pathologic grades obtained from patients in Shandong Provincial Hospital, we found that compared with normal brain and LGG tissues, transforming growth factor-β1 (TGF-β1) and NADPH oxidases 4 (NOX4) mRNA and protein expression levels in GBM tissues were significantly higher
We found that the LGG and GBM patients with high TGF-β1 or NOX4 expression had a worse prognosis than patients with low TGF-β1 or NOX4 expression in The Cancer Genome Atlas (TCGA) database (Figures 1(e) and 1(f))
Summary
Glioblastoma multiforme (GBM) is the most prevalent primary malignant tumors affecting the human brain with a median survival of 15 months [1]. Despite improvements in therapeutic technologies including surgical resection, adjuvant radiotherapy, and chemotherapy, patients with GBM have a poor clinical result and the molecular mechanisms responsible for the development of GBM have not yet been fully elucidated [2]. For these reasons, the identification of novel treatments to improve the available therapeutic options is essential for managing this disease. A total of seven NOX proteins have been identified, including NOX1-5 and DUOX1-2 [10] These enzymes are widely expressed in numerous tissues and have various functions, including roles in cell signaling, regulation of gene expression, cell death, differentiation, and growth. The expression and activity of NOX4 is regulated by TGF-β1 in many cell types [11, 12], but it is not reported that NOX4 expression is regulated by TGF-β1 in glioblastoma
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