Abstract
Glioblastoma (GBM) is characterized by severe hypoxic and acidic stress in an abnormal microenvironment. Monocarboxylate transporter (MCT)4, a pH-regulating protein, plays an important role in pH homeostasis of the glycolytic metabolic pathways in cancer cells. The present study showed that GBM exposure to hypoxic conditions increased MCT4 expression. We further analyzed the glioma patient database and found that MCT4 was significantly overexpressed in patients with GBM, and the MCT4 levels positively correlated with the clinico-pathological grades of gliomas. We further found that MCT4 knockdown abolished the hypoxia-enhanced of GBM cell motility and monocyte adhesion. However, the overexpression of MCT4 promoted GBM cell migration and monocyte adhesion activity. Our results also revealed that MCT4-regulated GBM cell motility and monocyte adhesion are mediated by activation of the serine/threonine-specific protein kinase (AKT), focal adhesion kinase (FAK), and epidermal growth factor receptor (EGFR) signaling pathways. Moreover, hypoxia mediated the acetylated signal transducer and activator of transcription (STAT)3 expression and regulated the transcriptional activity of hypoxia inducible factor (HIF)-1α in GBM cell lines. In a GBM mouse model, MCT4 was significantly increased in the tumor necrotic tissues. These findings raise the possibility for the development of novel therapeutic strategies targeting MCT4.
Highlights
Glioblastoma (GBM) is the most common primary malignant brain tumor of all primary brain and central nervous system neoplasms [1,2]
Using chromatin immunoprecipitation (ChIP) assays, we demonstrated that hypoxia inducible factor (HIF)-1α binding to the hypoxia response element (HRE) binding site on the MCT4 promoter under hypoxia was regulated by acetylation of STAT3
Our results showed that histone deacetylase (HDAC) inhibitors augmented hypoxia-induced HIF-1α and MCT4 protein expression in the GBM cells (Figure 6C)
Summary
Glioblastoma (GBM) is the most common primary malignant brain tumor of all primary brain and central nervous system neoplasms [1,2]. Upon initial diagnosis of GBM, standard treatment consists of maximal surgical resection, radiotherapy, and adjuvant chemotherapy with temozolomide [3]. The highly heterogeneous tumor microenvironment plays a substantial role in treatment responses [4]. Histological studies have shown that GBM is one of the most hypoxic and angiogenic tumors [5,6]. GBM relies on robust intra-tumoral oxygenation and a pH-regulating system that leads to hypoxia and acidosis and the ability of tumor cells to adapt to the hypoxic microenvironment [7,8], which offers a distinct evolutionary advantage towards an aggressive phenotype [9,10]. HIF-1α is involved in the adaptive response under
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