Targeting the glucose-regulated protein-78 abrogates Pten-null driven AKT activation and endometrioid tumorigenesis

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Rates of the most common gynecologic cancer, endometrioid adenocarcinoma (EAC), continue to rise, mirroring the global epidemic of obesity, a well-known EAC risk factor. Thus, identifying novel molecular targets to prevent and/or mitigate EAC is imperative. The prevalent Type 1 EAC commonly harbors loss of the tumor suppressor, Pten, leading to AKT activation. The major endoplasmic reticulum (ER) chaperone, GRP78, is a potent pro-survival protein to maintain ER homeostasis, and as a cell surface protein, is known to regulate the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. To determine whether targeting GRP78 could suppress EAC development, we created a conditional knockout mouse model using progesterone receptor-Cre-recombinase to achieve Pten and Grp78 (cPtenf/fGrp78f/f) deletion in the endometrial epithelium. Mice with a single Pten (cPtenf/f) deletion developed well-differentiated EAC by 4 weeks. In contrast, no cPtenf/fGrp78f/f mice developed EAC, even after more than 8 months of observation. Histologic examination of uteri from cPtenf/fGrp78f/f mice also revealed no complex atypical hyperplasia, a well-established EAC precursor. These histologic observations among the cPtenf/fGrp78f/f murine uteri also corresponded to abrogation of AKT activation within the endometrium. We further observed that GRP78 co-localized with activated AKT on the surface of EAC, thus providing an opportunity for therapeutic targeting. Consistent with previous findings that cell surface GRP78 is an upstream regulator of PI3K/AKT signaling, we show here that in vivo short-term systemic treatment with a highly specific monoclonal antibody against GRP78 suppressed AKT activation and increased apoptosis in the cPtenf/f tumors. Collectively, these findings present GRP78-targeting therapy as an efficacious therapeutic option for EAC.

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We thank the USC Norris Comprehensive Cancer Center Translational Pathology Core for tissue processing and the USC Research Center for Liver Diseases Cell and Tissue Imaging Core. We also thank the members of the Lee lab, particularly Wan-Ting Chen, Genyuan Zhu and Michelle Pong for their input and assistance throughout this project. This work was supported by the USC Department of Obstetrics & Gynecology Seed Grant (YGL), Stop Cancer Career Development Award (YGL), NIH Grant R01 CA027607 (ASL), NIH Grant K08 CA175161 (YGL) and NCI Cancer Center Support Grant (P30 CA014089, ASL/YGL). Microscopy at the Cell and Tissue Imaging Core of the USC Research Center for Liver Diseases was supported by NIH Grant P30 DK048522.

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Correspondence to Y G Lin or A S Lee.

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