The recent discovery that GRP78, traditionally regarded as a major endoplasmic reticulum (ER) chaperone and regulator of ER stress signaling, can also localize to the cell surface under pathophysiologic conditions such as cancer, changes the paradigm on how this protein may exert its pro-proliferative and anti- apoptotic function in cancer. In the past grant period, we established that GRP78 haploinsufficiency suppresses breast tumorigenesis through inhibition of tumor proliferation, angiogenesis and increased apoptosis. Through creation of a novel mutant mouse model with conditional biallelic deletion of both Grp78 and the tumor suppressor gene Pten, we discovered that not only is GRP78 critically required for prostate tumorigenesis and hematologic cancers, but is also required for PI3K/AKT activation in both types of cancer, both in vivo and in vitro. Cel surface GRP78 (sGRP78) is emerging as a co-receptor controlling cell signaling. In understanding how GRP78 regulates oncogenic signaling, we established that ER stress not only upregulates GRP78 but also actively promotes relocalization of GRP78 from the ER to the cell surface, and this process is regulated by the KDEL retrieval machinery. Taking advantage of cell surface localization of GRP78 in cancer cells but not in normal organs, we screened and identified a lead monoclonal antibody (MAb159) which specifically binds to cell surface GRP78, induces cancer cell apoptosis and suppresses tumor growth. Here we hypothesize that sGRP78 is a major effector of tumor growth and therapeutic resistance through its ability to regulate the PI3K/AKT signaling pathway and that targeting sGRP78 represents a novel and powerful approach for anti-PI3K therapy that will suppress tumor growth and alleviate drug resistance.
In Aim 1, we seek to understand the underlying molecular mechanisms that allow GRP78 to escape from the ER to the cell surface, through analysis of the functional domains of GRP78 required for surface localization and the integrity of the ER retrieval machinery, coupled with liv cell imaging of GRP78 mobilization.
In Aim 2, we will determine how sGRP78 regulates PI3K/AKT signaling by investigating the functional and physical interactions of sGRP78 with components of the PI3K pathway and the effect of targeting sGRP78 on other oncogenic pathways.
In Aim 3, we will directly test the role of sGRP78 in tumorigenesis and therapeutic resistance in spontaneous mouse cancer models and xenograft models using human cancer cell lines resistant to therapy. As a logical extension of our work on prostate cancer, we will utilize a novel Pten-null prostate cancer model which allows bioluminescence monitoring of cancer development, progression and recurrence after castration. Castration sensitive and resistant cells derived from this model will also be studied. The efficacy and safety of MAb159 will be tested in other cancer models, either alone or in combination therapy. Thus, this work not only addresses fundamental mechanisms but also has wide clinical implications.

Public Health Relevance

This proposal represents a first comprehensive study on the molecular mechanisms for cell surface localization of GRP78 and how the cell surface form of GRP78 serves as an upstream regulator of PI3K/AKT pathway, which is critical for cancer survival and resistance. This study will also address the efficacy and safety of a novel anti-cancer therapeutic antibody against cell surface GRP78 in the treatment of resistant cancers while sparing normal organs, which will have wide clinical implications.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Ogunbiyi, Peter
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University of Southern California
Schools of Medicine
Los Angeles
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Lee, Amy S (2014) Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer 14:263-76
Chen, Wan-Ting; Tseng, Chun-Chih; Pfaffenbach, Kyle et al. (2014) Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis. Hepatology 59:947-57
Zhu, Genyuan; Wang, Miao; Spike, Benjamin et al. (2014) Differential requirement of GRP94 and GRP78 in mammary gland development. Sci Rep 4:5390
Chen, Wan-Ting; Ha, Dat; Kanel, Gary et al. (2014) Targeted deletion of ER chaperone GRP94 in the liver results in injury, repopulation of GRP94-positive hepatocytes, and spontaneous hepatocellular carcinoma development in aged mice. Neoplasia 16:617-26
Gray, Michael J; Mhawech-Fauceglia, Paulette; Yoo, Eunjeong et al. (2013) AKT inhibition mitigates GRP78 (glucose-regulated protein) expression and contribution to chemoresistance in endometrial cancers. Int J Cancer 133:21-30
Luo, B; Lee, A S (2013) The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 32:805-18
Su, S-F; Chang, Y-W; Andreu-Vieyra, C et al. (2013) miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. Oncogene 32:4694-701
Wey, Shiuan; Luo, Biquan; Tseng, Chun-Chih et al. (2012) Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling. Blood 119:817-25
Lee, Eunjung; Nichols, Peter; Groshen, Susan et al. (2011) GRP78 as potential predictor for breast cancer response to adjuvant taxane therapy. Int J Cancer 128:726-31
Chen, Wan-Ting; Lee, Amy S (2011) Measurement and modification of the expression level of the chaperone protein and signaling regulator GRP78/BiP in mammalian cells. Methods Enzymol 490:217-33

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