BIX-01294 sensitizes renal cancer Caki cells to TRAIL-induced apoptosis through downregulation of survivin expression and upregulation of DR5 expression.

Cell Death Discov 2018 Dec 20;4:29. Epub 2018 Feb 20.

Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601 South Korea.

BIX-01294 (BIX), a G9a histone methyltransferase inhibitor, has been reported for its anti-proliferative and anticancer activities against various cancer cell lines. In this study, we investigated whether BIX could sensitize TRAIL-mediated apoptosis in various cancer cells. Combined treatment with BIX and TRAIL markedly induced apoptosis in human renal carcinoma (Caki, ACHN, and A498), breast carcinoma (MCF-7), and lung carcinoma (A549) cells. In contrast, BIX and TRAIL co-treatment did not induce apoptosis in normal cells, specifically mouse kidney cell (TCMK-1) and human skin fibroblast (HSF). BIX downregulated protein expression levels of XIAP and survivin at the post-translational level. Overexpression of survivin markedly blocked combined BIX and TRAIL treatment-induced apoptosis, but XIAP had no effect. Furthermore, BIX induced upregulation of DR5 expression at the transcriptional levels, and knockdown of DR5 expression using small interfering RNAs (siRNAs) markedly attenuated BIX and TRAIL-induced apoptosis. Interestingly, siRNA-mediated G9a histone methyltransferase knockdown also enhanced TRAIL-induced apoptosis in Caki cells. However, knockdown of G9a did not change expression levels of XIAP, survivin, and DR5. Therefore, BIX-mediated TRAIL sensitization was independent of histone methyltransferase G9a activity. Taken together, these results suggest that BIX facilitates TRAIL-mediated apoptosis via downregulation of survivin and upregulation of DR5 expression in renal carcinoma Caki cells. ▶ BIX facilitates TRAIL-mediated apoptosis in human renal carcinoma Caki cells. ▶ Downregulation of survivin contributes to BIX plus TRAIL-induced apoptosis. ▶ Upregulation of DR5 is involved in BIX plus TRAIL-mediated apoptosis. ▶ BIX-mediated TRAIL sensitization is independent of ROS production.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41420-018-0035-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841352PMC
December 2018

Publication Analysis

Top Keywords

dr5 expression
16
caki cells
16
trail-induced apoptosis
16
upregulation dr5
16
trail-mediated apoptosis
16
histone methyltransferase
12
downregulation survivin
12
carcinoma caki
12
bix trail
12
bix
12
renal carcinoma
12
apoptosis
11
expression levels
8
facilitates trail-mediated
8
cells ▶
8
levels xiap
8
sensitization independent
8
apoptosis human
8
bix trail-induced
8
human renal
8

Similar Publications