A small molecule regulator of tissue transglutaminase conformation inhibits the malignant phenotype of cancer cells
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William P. Katt1, Nicolas J. Blobel1, Svetlana Komarova2, Marc A. Antonyak1, Ichiro Nakano2 and Richard A. Cerione1,3
1Department of Molecular Medicine, Cornell University, Ithaca, NY, USA
2Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA
3Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA
Richard A. Cerione, email: [email protected]
Keywords: transglutaminase; glioblastoma; signaling; glioma stem cells; cancer
Received: July 25, 2018 Accepted: September 15, 2018 Published: September 28, 2018
The protein crosslinking enzyme tissue transglutaminase (tTG) is an acyltransferase which catalyzes transamidation reactions between two proteins, or between a protein and a polyamine. It is frequently overexpressed in several different types of human cancer cells, where it has been shown to contribute to their growth, survival, and invasiveness. tTG is capable of adopting two distinct conformational states: a protein crosslinking active (“open”) state, and a GTP-bound, crosslinking inactive (“closed”) state. We have previously shown that the ectopic expression of mutant forms of tTG, which constitutively adopt the open conformation, are toxic to cells. This raises the possibility that strategies directed toward causing tTG to maintain an open state could potentially provide a therapeutic benefit for cancers in which tTG is highly expressed. Here, we report the identification of a small molecule, TTGM 5826, which stabilizes the open conformation of tTG. Treatment of breast and brain cancer cell lines, as well as glioma stem cells, with this molecule broadly inhibits their transformed phenotypes. Thus, TTGM 5826 represents the lead compound for a new class of small molecules that promote the toxicity of cancer cells by stabilizing the open state of tTG.
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