Targeting cell surface-associated GRP78 enhances pancreatic cancer radiosensitivity by reducing YAP/TAZ protein signaling.

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2019-07-29

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Abstract

Ionizing radiation (IR) can promote migration and invasion of cancer cells, but the basis for this phenomenon has not been fully elucidated. IR increases expression of glucose-regulated protein 78kDa (GRP78) on the surface of cancer cells (CS-GRP78), and this up-regulation is associated with more aggressive behavior, radioresistance, and recurrence of cancer. Here, using various biochemical and immunological methods, including flow cytometry, cell proliferation and migration assays, Rho activation and quantitative RT-PCR assays, we investigated the mechanism by which CS-GRP78 contributes to radioresistance in pancreatic ductal adenocarcinoma (PDAC) cells. We found that activated α2-Macroglobulin (α2M*) a ligand of the CS-GRP78 receptor, induces formation of the AKT kinase (AKT)/DLC1 Rho-GTPase-activating protein (DLC1) complex and thereby increases Rho activation. Further, CS-GRP78 activated the transcriptional coactivators Yes-associated protein (YAP) and tafazzin (TAZ) in a Rho-dependent manner, promoting motility and invasiveness of PDAC cells. We observed that radiation-induced CS-GRP78 stimulates the nuclear accumulation of YAP/TAZ and increases YAP/TAZ target gene expressions. Remarkably, targeting CS-GRP78 with C38 monoclonal antibody (Mab) enhanced radiosensitivity and increased the efficacy of radiation therapy by curtailing PDAC cell motility and invasion. These findings reveal that CS-GRP78 acts upstream of YAP/TAZ signaling and promote migration and radiation-resistance in PDAC cells. We therefore conclude that, C38 Mab is a promising candidate for use in combination with radiation therapy to manage PDAC.

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10.1074/jbc.ra119.009091

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Gopal, Udhayakumar, Yvonne Mowery, Kenneth Young and Salvatore Vincent Pizzo (2019). Targeting cell surface-associated GRP78 enhances pancreatic cancer radiosensitivity by reducing YAP/TAZ protein signaling. The Journal of biological chemistry. pp. jbc.RA119.009091–jbc.RA119.009091. 10.1074/jbc.ra119.009091 Retrieved from https://hdl.handle.net/10161/19343.

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Scholars@Duke

Mowery

Yvonne Marie Mowery

Butler Harris Assistant Professor in Radiation Oncology
Pizzo

Salvatore Vincent Pizzo

Distinguished Professor of Pathology, in the School of Medicine

RESEARCH ABSTRACT
Studies from this laboratory identified cell surface expression of the molecular chaperone GRP78 as a major factor in prostate cancer and other malignancies.  Cell surface GRP78 functions as a signaling receptor promoting tumor proliferation and suppressing apoptosis.  Patients with a number of malignancies mount an autoimmune response to GRP78 and these antibodies, which bind to the NH2 terminal domains of GRP78, are receptor agonists whose appearance is a marker of poor prognosis.  More recently, we have shown that antibodies directed against the COOH-terminal domain of GRP78 are receptor antagonists which may have therapeutic potential for treating patients whose tumors express GRP78 on the cell surface.


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