Glycerol‐3‐phosphate acyltransferase 3‐mediated lipid droplets accumulation confers chemoresistance of colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most common malignancy worldwide. It is well known that lipid metabolism reprogramming contributes to the tumor progression. However, the lipid metabolic alterations and potential remodeling mechanism underlying the chemoresistance of CRC remain largely unclear. In this study, we compared the gene expression profiles of chemoresistant versus control CRC cells from the GEO database and identified a key factor, Glycerol‐3‐phosphate acyltransferase 3 (GPAT3), that promotes lipid droplet (LD) production and confers chemoresistance of CRC. With applying of HPLC–MS and molecular dynamics simulation, we also demonstrated that the activity of lysophosphatidic acid synthesis by GPAT3 was dependent on its acetylation at K316 site. In particular, GPAT3‐mediated LD accumulation inhibited immunogenic cell death of tumor, and thus facilitated CD8+ T‐cell exhaustion and malignant progression in mouse xenografts and hepatic‐metastasis tumors in CRC patients. High GPAT3 expression turned CRC cells into nonimmunogenic cells after (Oxaliplatin) Oxa treatment, which was supported by a decrease in cytotoxic IFN‐γ release and CD8+ T‐cell exhaustion. In conclusion, these findings revealed the role of GPAT3‐associated LD accumulation, which conferred a malignant phenotype (chemoresistance) and regulated the tumor microenvironment of CRC. These results suggest that GPAT3 is a potential target to enhance CRC chemosensitivity and develop novel therapeutic interventions.

Abstract

GPAT3 is responsible for G3P converting to LPA. It is the first step in TG synthesis and LD production. Oxa induces GPAT3 overexpression and LDs accumulation, which confers chemoresistance to CRC cells. Chemoresistant cells present a more malignant phenotype and suppress the cell killing effect of CD8+T cells, resulting in immune evasion and tumor recurrence