TY - JOUR
T1 - Endoplasmic reticulum stress protein GRP78 modulates lipid metabolism to control drug sensitivity and antitumor immunity in breast cancer
AU - Cook, Katherine L.
AU - Soto-Pantoja, David R.
AU - Clarke, Pamela A.G.
AU - Cruz, M. Idalia
AU - Zwart, Alan
AU - Wärri, Anni
AU - Hilakivi-Clarke, Leena
AU - Roberts, David D.
AU - Clarke, Robert
N1 - Publisher Copyright:
© 2016 AACR.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-15-2616
DO - 10.1158/0008-5472.CAN-15-2616
M3 - Article
C2 - 27698188
AN - SCOPUS:84989945682
VL - 76
SP - 5657
EP - 5670
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 19
ER -
