Blockade of cell volume regulatory protein NKCC1 increases TMZ-induced glioma apoptosis and reduces astrogliosis,Molecular Cancer Therapeutics

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Blockade of cell volume regulatory protein NKCC1 increases TMZ-induced glioma apoptosis and reduces astrogliosis
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2020-05-11 , DOI: 10.1158/1535-7163.mct-19-0910
Lanxin Luo _{1,

2,

3} , Xiudong Guan _{3,

4,

5,

6,

7} , Gulnaz Begum ₃ , Dawei Ding ₃ , Jenesis Gayden ₈ , Md Nabiul Hasan ₃ , Victoria M Fiesler ₃ , Jacob Dodelson ₃ , Gary Kohanbash _{9,

10} , Baoli Hu ₉ , Nduka M Amankulor ₉ , Wang Jia _{4,

5,

6,

7} , Maria G Castro ₁₁ , Baoshan Sun _{2,

12} , Dandan Sun _{3,

13}

Affiliation

School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Chinese National Clinical Research Center for Neurological Diseases, Beijing, China.
Beijing Neurosurgical Institute, Beijing, China.
Chinese Glioma Genome Atlas Network, Beijing, China.
Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Neurosurgery and Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan.
Pólo Dois Portos, Instituto National de Investigação Agrária e Veterinária, I.P., Quinta da Almoinha, Dois Portos, Portugal.
Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, Pennsylvania.

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.

更新日期：2020-05-11

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