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Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling.

Publication ,  Journal Article
Gopal, U; Mowery, Y; Young, K; Pizzo, SV
Published in: J Biol Chem
September 20, 2019

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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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

September 20, 2019

Volume

294

Issue

38

Start / End Page

13939 / 13952

Location

United States

Related Subject Headings

  • YAP-Signaling Proteins
  • Transcriptional Activation
  • Transcription Factors
  • Radiation Tolerance
  • Pancreatic Neoplasms
  • Humans
  • Heat-Shock Proteins
  • Gene Expression
  • Endoplasmic Reticulum Chaperone BiP
  • Dose-Response Relationship, Radiation
 

Citation

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Gopal, U., Mowery, Y., Young, K., & Pizzo, S. V. (2019). Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling. J Biol Chem, 294(38), 13939–13952. https://doi.org/10.1074/jbc.RA119.009091
Gopal, Udhayakumar, Yvonne Mowery, Kenneth Young, and Salvatore Vincent Pizzo. “Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling.J Biol Chem 294, no. 38 (September 20, 2019): 13939–52. https://doi.org/10.1074/jbc.RA119.009091.
Gopal U, Mowery Y, Young K, Pizzo SV. Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling. J Biol Chem. 2019 Sep 20;294(38):13939–52.
Gopal, Udhayakumar, et al. “Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling.J Biol Chem, vol. 294, no. 38, Sept. 2019, pp. 13939–52. Pubmed, doi:10.1074/jbc.RA119.009091.
Gopal U, Mowery Y, Young K, Pizzo SV. Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling. J Biol Chem. 2019 Sep 20;294(38):13939–13952.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

September 20, 2019

Volume

294

Issue

38

Start / End Page

13939 / 13952

Location

United States

Related Subject Headings

  • YAP-Signaling Proteins
  • Transcriptional Activation
  • Transcription Factors
  • Radiation Tolerance
  • Pancreatic Neoplasms
  • Humans
  • Heat-Shock Proteins
  • Gene Expression
  • Endoplasmic Reticulum Chaperone BiP
  • Dose-Response Relationship, Radiation