Transglutaminase 2 inhibition found to induce p53 mediated apoptosis in renal cell carcinoma

Abstract

Renal cell carcinoma (RCC), the predominant form of kidney cancer, is characterized by high resistance to radiation and chemotherapy. This study shows that expression of protein cross-linking enzyme transglutaminase 2 (TGase 2) is markedly increased in 7 renal cell carcinoma (RCC) cell lines in comparison to HEK293 and other cancer cell lines, such as NCI 60. However, the key role of TGase 2 in RCC was not clear. The down-regulation of TGase 2 was found to stabilize p53 expression, thereby inducing a 3- to 10-fold increase in apoptosis for 786-O, A498, CAKI-1, and ACHN cell lines by DAPI staining. MEF cells from TGase 2(-/-) mice showed stabilized p53 under apoptotic stress to compare to MEFs from wild-type mice. TGase 2 directly cross links the DNA binding domain of p53, leading to p53 depletion via autophagy in RCC. TGase 2 and p53 expression showed an inverse relationship in RCC cells. This finding implies that induced expression of TGase 2 promotes tumor cell survival through p53 depletion in RCC.

Keywords: autophagy; kidney cancer; protein cross-linking.