Transglutaminase Is Required for Epidermal Squamous Cell Carcinoma Stem Cell Survival.
Cancer stem cells are thought to be responsible for rapid tumor growth, metastasis, and enhanced tumor survival following drug treatment. For this reason, there is a major emphasis on identifying proteins that can be targeted to kill cancer stem cells or control their growth, and transglutaminase type II (TGM2/TG2) is such a target in epidermal squamous cell carcinoma. TG2 was originally described as a transamidase in the extracellular matrix that crosslinks proteins by catalyzing ε-(γ-glutamyl)lysine bonds. However, subsequent studies have shown that TG2 is a GTP-binding protein that plays an important role in cell signaling and survival. In the present study, TG2 shows promise as a target for anticancer stem cell therapy in human squamous cell carcinoma. TG2 was determined to be highly elevated in epidermal cancer stem cells (ECS cells), and TG2 knockdown or suppression of TG2 function with inhibitors reduced ECS cell survival, spheroid formation, Matrigel invasion, and migration. The reduction in survival is associated with activation of apoptosis. Mechanistic studies, using TG2 mutants, revealed that the GTP-binding activity is required for maintenance of ECS cell growth and survival, and that the action of TG2 in ECS cells is not mediated by NF-κB signaling.


CONCLUSIONS
This study suggests that TG2 has an important role in maintaining cancer stem cell survival, invasive, and metastatic behavior and is an important therapeutic target to reduce survival of cancer stem cells in epidermal squamous cell carcinoma.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
Matthew L
ML
Fisher
Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada.
Jeffrey W
JW
Keillor
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
Wen
W
Xu
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland. Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland. Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland. Marlene and Stewart Greenebaum Cancer, University of Maryland School of Medicine, Baltimore, Maryland. reckert@umaryland.edu CKerr@som.umaryland.edu.
Richard L
RL
Eckert
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland. Marlene and Stewart Greenebaum Cancer, University of Maryland School of Medicine, Baltimore, Maryland. reckert@umaryland.edu CKerr@som.umaryland.edu.
Candace
C
Kerr
D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction / Q000187:drug effects; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016328:NF-kappa B; C000717608:TGM2 protein, human; D006160:Guanosine Triphosphate; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C105804:transglutaminase 1; D019204:GTP-Binding Proteins