Autocrine motility factor peptide enhances curcumin/tetrahydrocurcumin activity against colorectal cancer cells in association with glucose-6-phosphate dehydrogenase downregulation and oxidative stress

Abstract Current therapeutic approaches for colorectal cancer (CRC) face significant limitations, including drug resistance, adverse effects, and high costs. Autocrine motility factor (AMF), the extracellular form of glucose-6-phosphate isomerase, exhibits paradoxical dual functionality as both a growth activator and inhibitor. This study examined the inhibitory effects of tetradecapeptides derived from AMF variants on the proliferation of HT-29 and SW620 CRC cells. Among six AMF peptides tested (AAP, HGP, HTP, SKP, AKP, and KAP), KAP showed the strongest growth inhibition, associated with downregulation of glucose-6-phosphate dehydrogenase (G6PD) and increased reactive oxygen species (ROS) production. Notably, combining KAP with curcumin (CUR) or its derivative tetrahydrocurcumin (THC) markedly reduced the viability of CRC cells that showed limited sensitivity to CUR and THC monotherapy. Furthermore, KAP elevated intracellular accumulation of fluorescent CUR, suggesting possible modulation of membrane transporter activity involved in xenobiotic efflux. These findings suggest that the combination of human-origin AMF peptides and plant-origin CUR/THC may represent a promising natural strategy for CRC treatment, warranting further preclinical investigation.