Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

• Published in: Oncogene Vol. 24; no. 46; pp. 6877 - 6889
• Main Authors: EUN HEE KIM, HEE SUE KIM, KIM, Seung U, EUN JOO NOH, LEE, Jong-Soo, KYEONG SOOK CHOI
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 20.10.2005; Nature Publishing Group
• Subjects: Ageing, cell death; Apoptosis; Apoptosis - physiology; Apoptosis Regulatory Proteins - physiology; Astrocytes; Astrocytes - cytology; Base Sequence; Bcl-2 protein; Bcl-x protein; Biological and medical sciences; Brain cancer; Butyric Acid - pharmacology; Cancer therapies; Caspase; Caspase inhibitors; Caspase-3; Cdc2 protein; CDC2 Protein Kinase - antagonists & inhibitors; Cell cycle; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin A; Cyclin B; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cytotoxicity; DNA Primers; Down-Regulation - physiology; Drug dosages; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Glioma; Glioma - metabolism; Glioma - pathology; Glioma cells; Histone Deacetylase Inhibitors; Humans; IAP protein; Inhibitor of Apoptosis Proteins; Kinases; Leukemia; Ligands; Medical sciences; Membrane Glycoproteins - physiology; Microtubule-Associated Proteins - physiology; Molecular and cellular biology; Neoplasm Proteins - physiology; Neurology; Proteins; Proteolysis; Reverse Transcriptase Polymerase Chain Reaction; Sodium; Sodium butyrate; Survivin; TNF-Related Apoptosis-Inducing Ligand; TRAIL protein; Tumor Necrosis Factor-alpha - physiology; Tumors of the nervous system. Phacomatoses; X-Linked Inhibitor of Apoptosis Protein - physiology; XIAP protein; South Korea; Human; Nervous system diseases; Glioma; Central nervous system disease; Tumor; Inhibition; Carcinogenesis; Apoptosis; Butyrate
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1208851

In TNF-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, co-treatment with nontoxic doses of sodium butyrate and TRAIL resulted in a marked increase of TRAIL-induced apoptosis. This combined treatment was also cytotoxic to glioma cells overexpressing Bcl-2 or Bcl-xL, but not to normal human astrocytes, thus offering an attractive strategy for safely treating resistant gliomas. Cotreatment with sodium butyrate facilitated completion of proteolytic processing of procaspase-3 that was partially blocked by treatment with TRAIL alone. We also found that treatment with sodium butyrate significantly decreased the protein levels of survivin and X-linked inhibitor of apoptosis protein (XIAP), two major caspase inhibitors. Overexpression of survivin and XIAP attenuated sodium butyrate-stimulated TRAIL-induced apoptosis, suggesting its involvement in conferring TRAIL resistance to glioma cells. Furthermore, the kinase activities of Cdc2 and Cdk2 were significantly decreased following sodium butyrate treatment, accompanying downregulation of cyclin A and cyclin B, as well as upregulation of p21. Forced expression of Cdc2 plus cyclin B, but not Cdk2 plus cyclin A, attenuated sodium butyrate/TRAIL-induced apoptosis, overriding sodium butyrate-mediated downregulation of survivin and XIAP. Therefore, Cdc2-mediated downregulation of survivin and XIAP by sodium butyrate may contribute to the recovery of TRAIL sensitivity in glioma cells.