Propranolol suppresses bladder cancer by manipulating intracellular pH via NHE1

BACKGROUND: In recent years, a large number of clinical and epidemiological studies have revealed the anti-cancer activity of propranolol in solid tumors, though the underline mechanism is yet to be clarified. METHODS: The proliferation of bladder cancer cells treated with propranolol was detected by MTS assays. In vivo tumor xenograft experiments were used to observe the effect of propranolol on bladder cancer growth in mice. The expression levels of Na(+)/H(+) exchanger (NHE1) was measured by western blot. The frequency of CD8(+) T cells and CD4(+) T cells were detected via flow cytometry. RESULTS: In this study, propranolol inhibited the expression of NHE1 and sequentially led to a decrease of intracellular pH to 5.88 in MB49 cells and 6.85 in 5637 cells, thereafter, inhibited cell viability and induced apoptosis. Furthermore, propranolol inhibited the growth of bladder cancer in mice xenograft model. Flow cytometry found that the frequency of CD8(+) T cells (34.58±2.11 vs. 32.34±0.6, P=0.35) and CD4(+) T cells (57.80±2.45 vs. 51.44±0.79, P=0.06) in the spleen did not change compared with the control group, while the expression of IFN-γ, GZMB and T-bet secreted by CD8(+) T cells increased respectively (IFN-γ 7.3±0.17 vs. 3.37±0.58, P=0.0017; GZMB 16.66±2.13 vs. 4.53±0.62, P=0.0034; T-bet 3.62±0.35 vs. 1.74±0.26, P=0.0027). Meantime, the expression of FoxP3 on CD4(+) T cells decreased both in spleen and tumor tissue (1.53±0.11 vs. 0.91±0.1, P=0.004; 4.52±0.48 vs. 1.76±0.40, P=0.003). CONCLUSIONS: These results suggested that propranolol exerted anti-proliferation and pro-apoptosis effects in bladder cancer cell by inhibiting Na(+)/H(+) exchange and activated systemic anti-tumor immune response in vivo.