IGFBP5 suppresses colorectal cancer stemness and carcinogenesis via binding to GPR182 and inhibiting PKCα/AKT/P70S6K axis.

Excessive proliferation of crypt stem cells represents a crucial hallmark in colorectal tumorigenesis. G protein-coupled receptor 182 (GPR182), a recently partially "deorphanized" G protein-coupled receptor (GPCR), has emerged as a pivotal modulator in gastrointestinal tumors. However, its roles and underlying mechanism in colorectal tumors remain unclear, primarily due to the absence of identified endogenous ligands. In this study, we identified Insulin like growth factor binding protein 5 (IGFBP5) as a novel endogenous ligand for GPR182. GPR182 mRNA and protein expression levels were significantly up-regulated in cancer stem cells of colorectal tissues or cell lines. Functional assays revealed that IGFBP5 inhibited growth of intestinal crypt organoids and cancer stem cell spheres. In APCMin/+ mice, IGFBP5 administration attenuated the tumor development while co-administration of GPR182 knockdown adeno-associated virus (AAV) abrogated this phenotype. Consistently, systemic IGFBP5 knockout markedly accelerated tumorigenesis and shortened survival time in APCMin/+ mice. Mechanistic investigations demonstrated that IGFBP5's engagement with GPR182 induced inhibition of AKT/P70S6K pathway via Protein kinase C alpha (PKCα) dephosphorylation. Together, these findings elucidate the suppressive role of IGFBP5 in colorectal cancer (CRC) stem cells via GPR182/PKCα/AKT/P70S6K axis, highlighting IGFBP5 implementation a promising strategy for CRC.