SLC18A3 promoted renal cancer development through acetylcholine/cAMP signaling

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) signal-ing. 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 synap-tic 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.