Abstract SY13-03: GRP78/BiP: Cancer's comrade in crime
Authors: Lee Amy S. , Shen Jieli , Rangel Daisy , Tseng Chun-Chih , Tsai Yuan Li , Ha Dat P. , Zhao He , Dubeau Louis 
Published: July 2017

Abstract
The 78 kDa glucose-regulated protein (GRP78), also referred to as BiP/HSPA5, is a major endoplasmic reticulum (ER) chaperone with antiapoptotic properties and also serves as a regulator of ER stress signaling (1). Tumor cells are subjected to ER stress due to intrinsic factors such as genetic mutations, altered metabolism and hyperproliferation, as well as extrinsic factors in the tumor microenvironment including oxygen and nutrient deprivation (2). As an adaptive measure, cancer cells turn on the unfolded protein response (UPR), and ER stress induction of GRP78 in cancer cells represents a major prosurvival response, suppressing apoptosis while promoting proliferation and invasiveness. Thus, GRP78 is an emerging target for therapy to blunt cancer development, progression, and drug resistance. GRP78 conditional knockout mouse models further established the requirement of GRP78 in solid and blood tumorigenesis driven by mutation of the tumor suppressor gene PTEN and that GRP78 is an upstream regulator of the PI3K/AKT/S6 pathway (3,4).
KRAS is commonly mutated in various cancers, including pancreatic adenocarcinoma (PDAC) and lung cancer, and thus far is deemed “undruggable”. We discovered that haploinsufficiency of a single moiety, GRP78, while having no effect on the normal pancreas, is sufficient to impede acinar-to-ductal metaplasia, block oncogenic signaling, curb PDAC progression, and prolong survival. Similarly, Grp78 haploinsufficiency is able to suppress mutant KRAS-driven lung cancer development. Further, we recently established that ER stress can actively promote cell surface localization of GRP78, where it assumes novel co-receptor functions with cell surface protein partners in regulating signal transduction pathways (5). Our studies uncover that csGRP78 interacts with specific cell surface signaling partner proteins and through those interactions impacts cancer cell adhesion, polarity, migration, and survival.
References
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3. Fu Y, Wey S, Wang M, Ye R, Liao CP, Roy-Burman P, et al. Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium. Proc Natl Acad Sci USA 2008;105:19444-9.
4. Wey S, Luo B, Tseng CC, Ni M, Zhou H, Fu Y, et al. Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling. Blood 2012;119:817-25.
5. Tsai YL, Zhang Y, Tseng CC, Stanciauskas R, Pinaud F, Lee AS. Characterization and mechanism of stress-induced translocation of 78-kilodalton glucose-regulated protein (GRP78) to the cell surface. J Biol Chem 2015;290:8049-64.
Citation Format: Amy S. Lee, Jieli Shen, Daisy Rangel, Chun-Chih Tseng, Yuan Li Tsai, Dat P. Ha, He Zhao, Louis Dubeau. GRP78/BiP: Cancer's comrade in crime [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2017-SY13-03