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.
Highlights
Ionizing radiation (IR) can promote migration and invasion of cancer cells, but the basis for this phenomenon has not been fully elucidated
To examine the impact of the ␣2M*/CS-glucose-regulated protein 78kDa (GRP78) axis on pancreatic ductal adenocarcinoma (PDAC) cell motility and invasion, we targeted CS-GRP78 by utilizing C38 mAb, scrambled (Scr) peptide, and GRP78 peptide derived from the GRP78 primary amino acid sequence (Leu98–Leu115), as described in our previous publication [8]
These results suggest that the promotility function of CS-GRP78 in PDAC cells is mediated through the Rho GTPase– dependent pathway
Summary
Ionizing radiation (IR) can promote migration and invasion of cancer cells, but the basis for this phenomenon has not been fully elucidated. 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 show that targeting CS-GRP78 with C38 mAb enhances the efficacy of radiotherapy by curtailing PDAC cell motility and invasion These data define a previously unknown mechanism of YAP/TAZ activation by CS-GRP78 and describe a new radiation-dependent role of YAP/TAZ to enhance PDAC cell motility and invasion. Together these studies indicate that targeting CS-GRP78 by C38 mAb might be employed as a potential therapeutic intervention in curtailing PDAC cell motility and enhancing radiosensitization
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