Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type I receptor in bladder cancer

BACKGROUND: We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type I receptor (ATIR) after the development of acquired platinum resistance in bladder cancer. METHODS: Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months. RESULTS: Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher ATIR expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased ATIR expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of ATIR blockade at suppressing the growth of platinum-resistant xenograft model. CONCLUSION: Our findings indicate a new molecular mechanism for upregulated ATIR signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of ATIR blockade for platinum-resistant bladder cancers. British Journal of Cancer (2011) 105, 1331-1337. doi:10.1038/bjc.2011.399 www.bjcancer.com Published online 4 October 2011 (C) 2011 Cancer Research UK