A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

• Published in: International journal of molecular sciences Vol. 21; no. 7; p. 2493
• Main Authors: Kim, Soo-Youl, Keillor, Jeffrey W
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 03.04.2020; MDPI
• Subjects: Angiogenesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Binding sites; Breast cancer; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Cell death; clear cell renal cell carcinoma (ccRCC); Clear cell-type renal cell carcinoma; Depletion; Drug resistance; Drug Resistance, Neoplasm; Enzymes; Extracellular matrix; Gene Expression Regulation, Neoplastic - drug effects; Genes; GTP-Binding Proteins - drug effects; GTP-Binding Proteins - genetics; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kinases; Methylation; Molecular Targeted Therapy; Mutation; Neoplasia; Ovarian cancer; p53; p53 Protein; Phenotypes; Polymerization; Precision Medicine; Review; Roles; Therapeutic applications; therapeutic target; Transglutaminase 2; transglutaminase 2 (TGase 2); Transglutaminases - drug effects; Transglutaminases - genetics; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Vascular endothelial growth factor; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; therapeutic target; clear cell renal cell carcinoma (ccRCC); transglutaminase 2 (TGase 2); p53
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21072493

In a recent report, no significance of transglutaminase 2 (TGase 2) was noted in the analyses of expression differences between normal and clear cell renal cell carcinoma (ccRCC), although we found that knock down of TGase 2 induced significant p53-mediated cell death in ccRCC. Generally, to find effective therapeutic targets, we need to identify targets that belong specifically to a cancer phenotype that can be differentiated from a normal phenotype. Here, we offer precise reasons why TGase 2 may be the first therapeutic target for ccRCC, according to several lines of evidence. TGase 2 is negatively regulated by von Hippel-Lindau tumor suppressor protein (pVHL) and positively regulated by hypoxia-inducible factor 1-α (HIF-1α in renal cell carcinoma (RCC). Therefore, most of ccRCC presents high level expression of TGase 2 because over 90% of ccRCC showed inactivity through mutation and methylation. Cell death, angiogenesis and drug resistance were specifically regulated by TGase 2 through p53 depletion in ccRCC because over 90% of ccRCC express wild type p53, which is a cell death inducer as well as a HIF-1α suppressor. Although there have been no detailed studies of the physiological role of TGase 2 in multi-omics analyses of ccRCC, a life-long study of the physiological roles of TGase 2 led to the discovery of the first target as well as the first therapeutic treatment for ccRCC in the clinical field.