Kremen1 induces SEC24C/ATG9A-dependent cell death in cancer cells.
Kremen1 is a receptor for Dickkopf (DKK) ligands which are WNT inhibitors. It has also been reported to induce cancer cell death in the absence of its ligand, DKK1; however, the precise mechanism underlying Kremen1-mediated cell death remains unclear. Our observations indicate that Kremen1 induces a form of cell death characterized by non-apoptotic features, accompanied by the accumulation of numerous vesicles and autophagosomes. Through biotin-based proximity labeling for protein-protein interaction analysis, we identified SEC24C—a component of the COP-II complex—as a critical effector in Kremen1-induced autophagy and cell death. Furthermore, our data demonstrate that Kremen1 localizes in proximity to SEC24C and ATG9A following vesicular trafficking and promotes the interaction of SEC24C with ATG8, ERGIC, and ATG9A. This network of interactions may underlie the increased formation of autophagosomes and vacuoles that culminate in cell death. Given that DKK1 is frequently upregulated in cancer and correlates with poor prognosis, reactivating the Kremen1-dependent cell death pathway may represent a promising therapeutic strategy. Ongoing studies are comparing this pathway to other cell death modalities to evaluate its potential utility in cancer therapy.
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