To understand the role of the colonic extracellular Calcium-sensing Receptor (CaSR) in calcium chemoprotection against colon cancer, we activated the CaSR with 5 mM Ca²⁺ on HT-29 cells, an adenocarcinoma cell line. High Ca²⁺ stimulated the upregulation (as assessed by RT-PCR) and the secretion of Wnt5a (assessed by Western blot), a non-canonical Wnt family member. Inhibiting CaSR activity with siRNA duplex against the CaSR reduced CaSR protein and prevented the secretion of Wnt5a. Dominant negative CaSR (R185Q) or siRNA, blocked the high Ca²⁺-mediated inhibition of the -catenin reporter TOPFLASH. The CaSR/Wnt5a inhibition of -catenin reporter was prevented by dominant negative Ubiquitin ligase Siah2. In low calcium medium, overexpressing Wnt5a increased Siah2 amplicons and protein. Inducing the expression of full length APC prevented CaSR-mediated increases of Siah2 and Wnt5a. Overexpressing the orphan tyrosine kinase receptor Ror2 increased Wnt5a and CaSR-mediated inhibition of TOPFLASH. Conditioned medium from Wnt5a transfected cells added to HT-29 cells in low calcium medium inhibited the -catenin reporter. This inhibition was blocked dose-responsively by Frizzled-8/Fc chimeric antibody. Overexpression of Ror2 in HT-29 cells in low calcium medium increased the inhibition of -catenin reporter caused by recombinant Wnt5a protein compared with addition of Wnt5a protein alone. Our findings demonstrate that APC status plays a key role as a determinant of Wnt5a secretion and suggest that CaSR-mediated secretion of Wnt5a will inhibit defective Wnt signaling in APC-truncated cells in an autocine manner.