Tie Peng, Cheng Ji, Xue Miao-Xin, Yin Jian, Fu Guo, Duan Wan-Li
Department of Urology, Shaanxi Provincial People's Hospital Xi'an, Shaanxi Province, China.
Am J Cancer Res. 2022 Sep 15;12(9):4279-4289. eCollection 2022.
Renal cancer displays a high metastatic potential and a poor response to chemotherapy. However, the critical contributors to renal cancer development remain elusive. This study focused on acetylcholine (ACh) signaling. We identified the vesicular acetylcholine transporter (SLC18A3) that upregulates in patients with renal cancer. We further discovered that SLC18A3 enhanced the uptake of ACh, a classical neurotransmitter mediating synaptic transmission. The elevated ACh activated the protein kinase A (PKA)/cAMP-response element binding protein (CREB) pathway, which contributed to renal cancer cell proliferation and invasive migration. Consistently, SLC18A3 overexpression caused sustained tumor growth and increased lung metastases in A489-bearing mice. In summary, our study demonstrated that SLC18A3 contributed to cancer spread in an ACh/PKA/CREB-dependent manner, which may drive the design of efficacious treatment strategies.
肾癌具有很高的转移潜能，且对化疗反应不佳。然而，导致肾癌发展的关键因素仍不清楚。本研究聚焦于乙酰胆碱（ACh）信号传导。我们鉴定出在肾癌患者中上调的囊泡型乙酰胆碱转运体（SLC18A3）。我们进一步发现，SLC18A3增强了ACh的摄取，ACh是一种介导突触传递的经典神经递质。升高的ACh激活了蛋白激酶A（PKA）/环磷酸腺苷反应元件结合蛋白（CREB）信号通路，这促进了肾癌细胞的增殖和侵袭性迁移。同样，SLC18A3的过表达导致携带A489细胞的小鼠肿瘤持续生长并增加肺转移。总之，我们的研究表明，SLC18A3以ACh/PKA/CREB依赖的方式促进癌症扩散，这可能推动有效治疗策略的设计。
