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.