Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness
Abstract
Anterior Gradient 2 (AGR2) is an endoplasmic reticulum (ER)-resident protein that belongs to the protein disulphide isomerase (PDI) family, and whose expression and secretion are induced by stress. Extracellular (secreted) AGR2 has been proposed as a marker of ER stress-related proteostasis alterations. Cancer cells frequently overexpress intracellular AGR2 (iAGR2) and secrete extracellular AGR2 (eAGR2). These features are associated with tumour progression and may serve as potential biomarkers in epithelial ovarian cancer (EOC). To investigate the roles of both iAGR2 and eAGR2 in EOC, we first generated EOC cells overexpressing iAGR2 and secreting eAGR2. Antibodies blocking eAGR2 reduced the proliferation and migration of these overexpressing cells. Concurrently, supplementation of parental cells with recombinant eAGR2 partially rescued these properties, further supporting a functional extracellular role for AGR2 in EOC. Quantitative proteomics, complemented by analysis of the TCGA database, revealed that eAGR2 modulated the expression of proteins involved in autophagy. This suggests that eAGR2-induced signalling may enhance catabolic activity under stress conditions, thereby increasing nutrient availability and, in turn, facilitating protein synthesis. This was reflected in the increased translational activity observed in AGR2-overexpressing and eAGR2-stimulated cells. Our results highlight two distinct, compartmentalised roles for AGR2. Specifically, iAGR2 acts as an ER-resident PDI, enhancing protein folding and ER quality control. In a complementary manner, eAGR2 functions as a metabolic regulator that may relieve constraints on tumour cell aggressiveness by maintaining autophagic flux and promoting protein synthesis. Overall, these findings support a dual-compartment model in which iAGR2 couples ER proteostasis with the metabolic and translational stimulation mediated by eAGR2.
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BibTeX
@article{guilbard2026complementary,
title = {{Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness}},
author = {Marianne Guilbard and Saïd Taouji and Marc Aubry and Jacques Robert and Raphael Pineau and Valérie Velasco and Romane Florent and Louis-Bastien Weiswald and Cecile Hartog and Coriolan Lebreton and Alix Coulon and Sabrina Croce and Guillaume Babin and Cédric Chaveroux and Stéphanie Beq and Eric Chevet and Delphine Fessart and Frédéric Delom},
journal = {Oncogene},
year = {2026},
month = aug,
doi = {10.1038/s41388-026-03938-y},
url = {https://normandie-univ.hal.science/hal-05744441v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness
AU - Marianne Guilbard
AU - Saïd Taouji
AU - Marc Aubry
AU - Jacques Robert
AU - Raphael Pineau
AU - Valérie Velasco
AU - Romane Florent
AU - Louis-Bastien Weiswald
AU - Cecile Hartog
AU - Coriolan Lebreton
AU - Alix Coulon
AU - Sabrina Croce
AU - Guillaume Babin
AU - Cédric Chaveroux
AU - Stéphanie Beq
AU - Eric Chevet
AU - Delphine Fessart
AU - Frédéric Delom
PY - 2026
DA - 2026/08/10
JO - Oncogene
DO - 10.1038/s41388-026-03938-y
UR - https://normandie-univ.hal.science/hal-05744441v1
AB - Anterior Gradient 2 (AGR2) is an endoplasmic reticulum (ER)-resident protein that belongs to the protein disulphide isomerase (PDI) family, and whose expression and secretion are induced by stress. Extracellular (secreted) AGR2 has been proposed as a marker of ER stress-related proteostasis alterations. Cancer cells frequently overexpress intracellular AGR2 (iAGR2) and secrete extracellular AGR2 (eAGR2). These features are associated with tumour progression and may serve as potential biomarkers in epithelial ovarian cancer (EOC). To investigate the roles of both iAGR2 and eAGR2 in EOC, we first generated EOC cells overexpressing iAGR2 and secreting eAGR2. Antibodies blocking eAGR2 reduced the proliferation and migration of these overexpressing cells. Concurrently, supplementation of parental cells with recombinant eAGR2 partially rescued these properties, further supporting a functional extracellular role for AGR2 in EOC. Quantitative proteomics, complemented by analysis of the TCGA database, revealed that eAGR2 modulated the expression of proteins involved in autophagy. This suggests that eAGR2-induced signalling may enhance catabolic activity under stress conditions, thereby increasing nutrient availability and, in turn, facilitating protein synthesis. This was reflected in the increased translational activity observed in AGR2-overexpressing and eAGR2-stimulated cells. Our results highlight two distinct, compartmentalised roles for AGR2. Specifically, iAGR2 acts as an ER-resident PDI, enhancing protein folding and ER quality control. In a complementary manner, eAGR2 functions as a metabolic regulator that may relieve constraints on tumour cell aggressiveness by maintaining autophagic flux and promoting protein synthesis. Overall, these findings support a dual-compartment model in which iAGR2 couples ER proteostasis with the metabolic and translational stimulation mediated by eAGR2.
SN - 0950-9232
SN - 1476-5594
ER -