Angiotensin II type 1 receptor signaling promotes bladder cancer progression and its inhibition by Losartan

The renin-angiotensin system (RAS) plays a central role in regulating blood pressure and has recently been implicated in cancer biology. Although angiotensin II (AngII) receptor blockers (ARBs) have shown clinical benefit in bladder cancer, their mechanisms of action remain unclear. Here, we investigated the contribution of AngII type 1 receptor (AGTR1) to bladder cancer progression and assessed the therapeutic potential of the ARB losartan (LOS). In patients with primary non-muscle-invasive bladder cancer, intravesical recurrence following transurethral tumor resection correlated with AGTR1 expression levels. Public database analysis revealed that the expression of AGTR1 and its downstream kinases, extracellular signal-regulated kinase (ERK) 1 and ERK2, was associated with overall survival in bladder urothelial carcinoma. In AGTR1-overexpressing T24 bladder cancer cells, AngII promoted invasion and migration and upregulated neuronal nitric oxide synthase, without affecting proliferation. These effects were accompanied by rapid ERK phosphorylation alongside Akt dephosphorylation. RNA sequencing revealed that AGTR1 expression and AngII stimulation activated NF-κB, mTOR, and epithelial-mesenchymal transition (EMT) pathways. LOS suppressed these AngII-mediated responses, whereas the AngII-independent upregulation of EMT-related proteins and the enhancement of mitochondrial energy metabolism by AngII in AGTR1-overexpressing cells remained unaffected. In vivo, AGTR1 facilitated early tumor engraftment and promoted tumor progression, accompanied by reduced E-cadherin and elevated N-cadherin expression, with most of these changes suppressed by LOS treatment. In conclusion, our findings highlight the crucial role of AGTR1 in bladder cancer and support the repositioning of ARBs, such as LOS, as therapeutics for AGTR1-upregulated bladder cancer, while underscoring the importance of AGTR1 stratification for future clinical evaluation.