Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas.
Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion. We have identified the novel finding that treatment of glioblastoma cells with transglutaminase 2 inhibitors promotes cell death and enhances sensitivity to chemotherapy. Treatment with either the competitive transglutaminase 2 inhibitor, monodansylcadaverine, or with highly specific small-molecule transglutaminase 2 inhibitors, KCA075 or KCC009, results in induction of apoptosis in glioblastoma cells. Treatment with these transglutaminase 2 inhibitors resulted in markedly decreased levels of the prosurvival protein, phosphorylated Akt, and its downstream targets. These changes promote a proapoptotic profile with altered levels of multiple intracellular proteins that determine cell survival. These changes include decreased levels of the antiapoptotic proteins, survivin, phosphorylated Bad, and phosphorylated glycogen synthetase kinase 3beta (GSK-3beta), and increased levels of the proapoptotic BH3-only protein, Bim. In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-N'-bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone. Groups treated with transglutaminase 2 inhibitors showed an increased incidence of apoptosis determined with deoxynucleotidyl transferase-mediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas.
Yuan
Liya
L
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Choi
Kihang
K
Khosla
Chaitan
C
Zheng
Xiao
X
Higashikubo
Ryuji
R
Chicoine
Michael R
MR
Rich
Keith M
KM
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001391:Azo Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D000072224:Bcl-2-Like Protein 11; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology; D002103:Cadaverine / Q000031:analogs & derivatives / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D011503:Transglutaminases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D001391:Azo Compounds; C000606775:BCL2L11 protein, human; C107489:BIRC5 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D000077022:Survivin; C000717608:TGM2 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D019204:GTP-Binding Proteins; C008542:monodansylcadaverine; D002103:Cadaverine; D002330:Carmustine