RNA interference targeting adrenomedullin induces apoptosis and reduces the growth of human bladder urothelial cell carcinoma

Adrenomedullin (ADM) is a potent, long-lasting angiogenic peptide that was originally isolated from human pheochromocytoma. ADM signaling is of particular significance in endothelial cell biology because the peptide protects cells from apoptosis, and ADM has been shown to be pro-tumorigenic in that it stimulates tumor cell growth and angiogenesis. ADM may be involved in micro-vessel proliferation and partially in the release of hypoxia in solid tumors, contributing to the proliferation of tumor cells as well as local tumor invasion and metastasis. However, the effect of hypoxia-induced ADM expression in bladder cancer remains unclear. Here, we found that the levels of ADM protein in tumor tissue from patients with bladder urothelial cell carcinoma were significantly increased compared to the adjacent non-tumor bladder tissues (p < 0.01). Under hypoxic conditions, the expression of ADM was significantly elevated in a time-dependent manner in human bladder cancer cell lines. Furthermore, the knockdown of ADM by shRNA in T24 cells showed obvious apoptosis compared to untransfected controls (p < 0.0001). In addition, the combination of cisplatin and ADM-shRNA significantly reduces the tumor growth in vivo compared to treatment with cisplatin (p = 0.0046) or ADM-shRNA alone (p < 0.0001). These data suggest that ADM plays an important role in promoting bladder cancer cell growth under hypoxia and that the inhibition of ADM may provide a target for bladder cancer therapy.