Abstract
Glioma is one of the most common primary malignant tumors of the central nervous system accounting for approximately 40% of all intracranial tumors. Temozolomide is a conventional chemotherapy drug for adjuvant treatment of patients with high-risk gliomas, including grade II to grade IV. Our bioinformatic analysis of The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets and immunoblotting assay show that SLC12A2 gene and its encoded Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) protein are abundantly expressed in grade II-IV gliomas. NKCC1 regulates cell volume and intracellular Cl- concentration, which promotes glioma cell migration, resistance to temozolomide, and tumor-related epilepsy in experimental glioma models. Using mouse syngeneic glioma models with intracranial transplantation of two different glioma cell lines (GL26 and SB28), we show that NKCC1 protein in glioma tumor cells as well as in tumor-associated reactive astrocytes was significantly upregulated in response to temozolomide monotherapy. Combination therapy of temozolomide with the potent NKCC1 inhibitor bumetanide reduced tumor proliferation, potentiated the cytotoxic effects of temozolomide, decreased tumor-associated reactive astrogliosis, and restored astrocytic GLT-1 and GLAST glutamate transporter expression. The combinatorial therapy also led to suppressed tumor growth and prolonged survival of mice bearing GL26 glioma cells. Taken together, these results demonstrate that NKCC1 protein plays multifaceted roles in the pathogenesis of glioma tumors and presents as a therapeutic target for reducing temozolomide-mediated resistance and tumor-associated astrogliosis.
Highlights
The World Health Organization (WHO)-classified low-grade gliomas (LGG) consist of grade I and grade II tumors, while high-grade gliomas (HGG) consist of grade III and grade IV tumors [1]
Immunofluorescence staining illustrated that grade II gliomas exhibited relatively higher level of Naþ-Kþ-2ClÀ cotransporter isoform 1 (NKCC1) protein expression than grade III/IV (P < 0.05; Fig. 1C)
New reports recently revealed abundant expression of NKCC1 protein in various types of cancer cells, such as gastric cancer cells [25], prostate cancer cells [26], lung adenocarcinoma cells [27], esophageal squamous carcinoma cells [28], and brain tumor cells [29], which is associated with tumor cell proliferation, migration, and invasion
Summary
The World Health Organization (WHO)-classified low-grade gliomas (LGG) consist of grade I and grade II tumors, while high-grade gliomas (HGG) consist of grade III and grade IV tumors [1]. Recent studies show the association of NKCC1 protein with gliomas, especially relating to GBM cell migration and invasion [10, 12,13,14,15]. Naþ-Kþ-ClÀ Cotransporter in Glioma high SLC12A2 mRNA expression had a significantly shorter overall survival [14] These findings strongly indicate that NKCC1 protein likely uses the above signaling mechanisms to regulate glioma migration/invasion and progression. In two intracranial mouse syngeneic glioma models, temozolomide monotherapy significantly upregulated NKCC1 protein expression in glioma tumor cells as well as in tumor-associated reactive astrocytes. Our results demonstrate that NKCC1 protein plays multifaceted roles in the pathogenesis of glioma and presents a therapeutic target for reducing tumor-associated reactive astrogliosis and temozolomide resistance
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