Synergistic inhibitory effects of 5-aza-2′-deoxycytidine and cisplatin on urothelial carcinoma growth via suppression of TGFBI-MAPK signaling pathways

Abstract

This study aimed to reveal the gene transcriptional alterations, possible molecular mechanisms, and pathways involved in the synergy of 5-aza-2′-deoxycytidine (DAC) and Cisplatin (CDDP) in urothelial carcinoma (UC). Two UC cell lines, 5637 and T24, were used in the present study. A cDNA microarray was performed to identify critical genes involved in the synergistic mechanism of both agents against UC cells. The results showed that several key regulatory genes, such as interleukin 24 (IL24), fibroblast growth factor 1 (FGF1), and transforming growth factor beta induced (TGFBI), may play critical roles in the synergy of DAC and CDDP in UC. Pathway enrichment suggested that many carcinogenesis-related pathways, such as the ECM-receptor interaction and MAPK signaling pathways, may participate in the synergy of both agents. Our results suggest that TGF-β1 stimulates the phosphorylation of ERK1/2 and p38 by increasing TGFBI expression, and that the TGFBI-MAPK signaling pathway plays an important role in the synergy of DAC and CDDP against UC. Therefore, we revealed the synergistic mechanism of DAC and CDDP in UC. Several key regulatory genes play critical roles in the synergy of combined treatment, and the TGFBI-MAPK signaling pathway may be an important potential target of these two agents.