LPCAT2 controls chemoresistance in colorectal cancer

Abstract

Lipid droplets (LD) are now-well recognized as playing a role in cancer progression, however their potential role in chemoresistance remains largely unknown, particularly in colorectal cancer (CRC). We recently highlighted that LD accumulate in CRC cells under the control of lysophosphatidylcholine acyltransferase 2 (LPCAT2) enzyme expression. We also showed that chemotherapy-induced LD accumulation counteracts intrinsic and extrinsic cancer cell death activation.

Keywords: LPCAT2; Lipid droplets; chemoresistance; colorectal cancer; immunogenic cell death.

Figure 1.

LPCAT2-dependent lipid droplet accumulation drives chemotherapy response of colorectal cancer cells. A. In low LPCAT2 cells, FOX treatment promotes 1) ER stress leading to eIF2α-dependent activation of ICD signals with CRT-membrane exposure which binds to CD91 receptor initiating apoptotic cell uptake and maturation of dendritic cells. Mature DC in turn, could activate naïve CD8⁺ T cells with co-stimulatory factors CD80/86/MHC-I and CD28/TCR. This activation transduces signals for CD8⁺ T lymphocytes to migrate to the tumour site and produce cytotoxic cytokines such as IFNγ. B. In high LPCAT2 cells, FOX treatment induces LD production leading to 1) ER homeostasis 2) CRT sequestration into LD. Impairment of CRT membrane exposure is associated with the incapacity of cancer cells to induce ICD. Calreticulin: CRT; (cleaved-)caspase 8: (c-)Csp8; Dendritic cells: DC; (Phospho)-Eukaryotic translation initiation factor 2 alpha: (P-)eIF2α; Endoplasmic reticulum: ER; 5-Fluorouracil and Oxaliplatin combination: FOX; Immunogenic cell death: ICD; Interferon gamma: IFNγ; Lipid droplets: LD; lysophosphatidylcholine acyltransferase 2: LPCAT2; Major histocompatibility complex-I: MHC-I; Perilipin 2: PLIN2; Phosphatidylcholine: PC; T cell receptor: TCR.