B7-H3 Promotes Proliferation and Migration of Colorectal Cancer Cells by Regulating PYCR1 in the Proline Metabolism

Abstract

Proline metabolism plays an essential role in tumor development; however, its underlying mechanism in CRC remains elusive. B7-H3, an immune checkpoint member of the B7 immunoregulatory family, is aberrantly overexpressed in a wide variety of malignancies and is associated with a poor prognosis. In this study, we found that overexpression of B7-H3 effectively enhanced proline consumption rate and reduced glutamate production, while knockout of B7-H3 had inverse effects. Moreover, we also identified that B7-H3 increased proline consumption and decreased glutamate production by promoting the expression of Pyrroline- 5-carboxylate reductase 1 (PYCR1) in CRC cells and that PYCR1 is a crucial mediator of B7-H3-induced CRC proliferation and migration. Overexpression of PYCR1 or treatment of cells with PYCR1 inhibitors could reverse B7-H3-induced proline metabolism and B7-H3-induced tumor cell proliferation and migration. Furthermore, we confirmed the positive correlation between B7-H3 and PYCR1 expression in tumor tissues of CRC patients. Collectively, the present study highlighted a previously unrecognized mechanism of B7-H3-mediated rewiring of proline metabolism through increased expression of PYCR1 in CRC cells. These findings suggested that B7-H3 may serve as a novel prognostic factor and a promising therapeutic target for CRC.