Blocking Glycoprotein‐130 Pathway Decreases Bladder Cancer Growth

The most effective adjuvant agent for treating non‐muscle invasive bladder cancer is Bacillus Calmette‐Guerin (BCG). However, since the response to BCG is unpredictable, new treatments are required. Glycoprotein‐130 (GP130) is a transmembrane protein which is central to a number of signal transduction pathways involved in tumor growth and progression. We performed immunohistochemistry on a paraffin‐embedded human bladder cancer tissue microarray and showed that the level of GP130 expression was significantly higher in high grade bladder cancer specimens (2.40 +/‐ 0.18 relative units) than in low grade cancer specimens (1.67 +/‐ 0.16 relative units). We targeted and degraded GP130 with GP130 siRNA (siGP130) that was encapsulated in chitosan functionalized nanoparticles (NP‐CHs). Blocking the expression of GP130 in bladder cancer cells inhibited cell migration and viability as well as decreased the expression of downstream proteins. Nude mice were subcutaneously injected with bladder cancer cells and after two weeks of treatment with NP‐siGP130‐CH, the expression of GP130 and the expression of cytokeratin‐20 (CK20), an urothelial carcinoma marker associated with increasing tumor grade, was down‐regulated, and bladder tumors were significantly smaller (75%, 60%) than tumors receiving either PBS or NP‐CH controls, respectively. We have shown that GP130 expression is higher in high grade than low grade human bladder cancers and that blocking the GP130 pathway inhibits bladder cancer migration, viability and progression. This study was supported in part by the NIH grant 5RC1DK087015 (Weiss), NIH grant EB000487 (Saltzman), and a Pilot Grant from the Yale Comprehensive Cancer Center (Weiss).