The unfolded protein response is an endoplasmic reticulum stress pathway
mediated by the protein chaperone glucose regulated-protein 78 (GRP78).
Metabolic analysis of breast cancer cells shows that GRP78 silencing
increases the intracellular concentrations of essential polyunsaturated
fats, including linoleic acid. Accumulation of fatty acids is due to an
inhibition of mitochondrial fatty acid transport, resulting in a
reduction of fatty acid oxidation. These data suggest a novel role of
GRP78-mediating cellular metabolism. We validated the effect of
GRP78-regulated metabolite changes by treating tumor-bearing mice with
tamoxifen and/or linoleic acid. Tumors treated with linoleic acid plus
tamoxifen exhibited reduced tumor area and tumor weight. Inhibition of
either GRP78 or linoleic acid treatment increased MCP-1 serum levels,
decreased CD47 expression, and increased macrophage infiltration,
suggesting a novel role for GRP78 in regulating innate immunity. GRP78
control of fatty acid oxidation may represent a new homeostatic function
for GRP78. Cancer Res; 76(19); 5657-70. ©2016 AACR.