Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling Signal Transduction
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 ra...
Conditions: Pancreatic Cancer; Pancreatic Adenocarcinoma Interventions: Radiation: Stereotactic Body Radiation Therapy (SBRT); Drug: FOLFIRINOX Sponsor: Indiana University Withdrawn
AbstractPurposePancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of
Conditions: Metastatic Pancreatic Adenocarcinoma; Refractory Pancreatic Adenocarcinoma; Stage IV Pancreatic Cancer AJCC v8 Interventions: Biological: Nivolumab; Radiation: Radiation Therapy; Drug: TLR9 Agonist SD-101 Sponsors: University of California, Davis; National Cancer Institute (NCI); Bristol-Myers Squibb; Dynavax Technologies Corporation Not yet recruiting