The intelectin 1-bestrophin-2-glutamate axis regulates glutamate homeostasis and suppresses colorectal cancer progression.

Colorectal cancer (CRC) is a highly prevalent malignancy with a poor prognosis, and metabolic reprogramming (eg, glutamic acid metabolism) drives its progression. However, the key regulators of glutamic acid homeostasis in CRC remain undefined. We analyzed the expression and prognostic significance of bestrophin-2 (BEST2) and intelectin 1 (ITLN1) using The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Stable cell lines with BEST2/ITLN1/glutamine synthetase (GS) overexpression or knockdown were constructed, and functional assays including Cell Counting Kit-8, flow cytometry, and ELISA were performed to explore their roles in cell proliferation, apoptosis, and glutamic acid metabolism. Coimmunoprecipitation/immunofluorescence were used to validated BEST2-GS interaction. A nude mouse xenograft model was used to confirm the in vivo effects of the ITLN1-BEST2-GS axis. BEST2 and ITLN1 were downregulated in CRC tissues, and their expression correlated with a favorable prognosis in patients with CRC. BEST2 suppressed CRC cell proliferation and promoted apoptosis by reducing intracellular glutamic acid levels, which was mediated by its membrane-localized interaction with GS to modulate GS activity. ITLN1 acted as an upstream positive regulator of BEST2 by enhancing its promoter activity and exerted tumor-suppressive effects in a BEST2-dependent manner. The ITLN1-BEST2-GS axis orchestrated glutamic acid homeostasis, and ITLN1 overexpression significantly inhibited xenograft tumor growth in nude mice. The ITLN1-BEST2-GS axis regulates glutamic acid metabolism to suppress CRC progression, thus identifying novel potential therapeutic targets for this malignancy. SIGNIFICANCE STATEMENT: The intelectin 1-bestrophin-2-glutamine synthetase axis modulates glutamic acid metabolism and exerts a tumor-suppressive effect in colorectal cancer.