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

dc.contributor.author

Gopal, Udhayakumar

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Mowery, Yvonne

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Young, Kenneth

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Pizzo, Salvatore Vincent

dc.date.accessioned

2019-09-27T15:34:51Z

dc.date.available

2019-09-27T15:34:51Z

dc.date.issued

2019-07-29

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2019-09-27T15:34:50Z

dc.description.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.

dc.identifier

RA119.009091

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0021-9258

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1083-351X

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https://hdl.handle.net/10161/19343

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eng

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Elsevier BV

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The Journal of biological chemistry

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10.1074/jbc.ra119.009091

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70 kilodalton heat shock protein (Hsp70)

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C38 Mab

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CS-GRP78

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YAP/TAZ signaling

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cell signaling

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cell surface receptor

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pancreatic ductal adenocarcinoma (PDAC)

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phosphotyrosine signaling

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radiation therapy

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selective internal radiation therapy (SIRT)

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tumor cell biology

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Mowery, Yvonne|0000-0002-9839-2414

pubs.begin-page

jbc.RA119.009091

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jbc.RA119.009091

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School of Medicine

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Duke

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Pathology

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Clinical Science Departments

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Duke Cancer Institute

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Institutes and Centers

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Radiation Oncology

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