RESUMEN
GRP78 is a protein that acts as a chaperone within the endoplasmic reticulum (ER) and has multiple functions. It is induced by stress and abets cells from survival. Despite, multiple Stress conditions like ER, chronic psychological and nutritional stress, hypoxia, chemotherapy, radiation therapy, and drug resistance induce cell surface GRP78 (CS-GRP78) expression in cancer cells. Further, CS-GRP78 is associated with increased malignancy and resistance to anti-cancer therapies and is considered a high-value druggable target. Recent preclinical research suggests that targeting CS-GRP78 with anti-GRP78 monoclonal antibodies (Mab) in combination with other agents may be effective in reversing the failure of chemotherapy, radiotherapy, or targeted therapies and increasing the efficacy of solid tumors treatment. This article will review recent evidence on the role of CS-GRP78 in developing resistance to anti-cancer treatments and the potential benefits of combining anti-GRP78 Mab with other cancer therapies for specific patient populations. Furthermore, our limited understanding of how CS-GRP78 regulated in human studies is a major drawback for designing effective CS-GRP78-targeted therapies. Hence, more research is still warranted to translate these potential therapies into clinical applications.
RESUMEN
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.