Ligation of cell surface GRP78 with antibody directed against the COOH-terminal domain of GRP78 suppresses Ras/MAPK and PI 3-kinase/AKT signaling while promoting caspase activation in human prostate cancer cells.

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We have previously shown that treatment of prostate cancer and melanoma cells expressing GRP78 on their cell surface with antibody directed against the COOH-terminal domain of GRP78 upregulates and activates p53 causing decreased cell proliferation and upregulated apoptosis. In this report, we demonstrate that treatment of 1-LN prostate cancer cells with this antibody decreases cell surface expression of GRP78, Akt(Thr308) and Akt(Ser473) kinase activities and reduces phosphorylation of FOXO, and GSK3beta. This treatment also suppresses activation of ERK1/2, p38 MAPK and MKK3/6; however, it upregulates MKK4 activity. JNK, as determined by its phosphorylation state, is subsequently activated, triggering apoptosis. Incubation of cells with antibody reduced levels of anti-apoptotic Bcl-2, while elevating pro-apoptotic BAD, BAX and BAK expression as well as cleaved caspases-3, -7, -8 and -9. Silencing GRP78 or p53 gene expression by RNAi prior to antibody treatment abrogated these effects. We conclude that antibody directed against the COOH-terminal domain of GRP78 may prove useful as a pan suppressor of proliferative/survival signaling in cancer cells expressing GRP78 on their cell surface.







Uma Kant Misra

Professor Emeritus of Pathology
  1. Biology of α2MSR: Ligands binding and their regulation, receptor upregulation, defining signaling cascades components, modulation of ser/thr/tyr kinase activities, cellular responses (mitogenesis, gene expression), physiological relevance.

    2. Receptor activation, and membrane phospholipases - PLA2, PI-PLCb, PI-PLCg, PC-PLC, PLD, sphingomyelinase, and ceramide signaling, regulation, role in mitogenesis.

    3. α2MSR and malignancy - Prostate cancer cell line e.g. 1LN, PC3, LnCap as model. Modulation of cellular responses by inhibitors of down stream signaling cascades, a2MSR and p53 (tumor suppressor gene) expression.

    4. Cations, α2MSR and genotoxicity - bivalen and trivalen cations and binding of α2M* to α2MSR, signaling cascades components and their regulation, mitogenesis.

    5. Isolation, purification and characterization of α - Autophosphorylation of the receptor on ligands binding, amino acid residues involved in receptor activation, mechanism of receptor desensitization, modulators/coactivators binding domains on the receptor, differences between LRP/α2MR and α2MSR, transfection studies.

    6. α2MSR and neuronal development -

    7. Internalization and proteosomies targeting of alpha-2-macroglobulin signaling receptor- A possible metabolic advantage for the isolation of α2MSR during its proteosome targeting.

    8. Cadmium and development of prostate malignancy-use of human prostate cancer cell liens as model. Delineating the role of farnesyl transferase, p21-Ras activation, MAPK and PI 3-kinase signaling cascades, transcription factors and early response genes in malignancy development.

Salvatore Vincent Pizzo

Distinguished Professor of Pathology, in the School of Medicine

Studies from this laboratory identified cell surface expression of the molecular chaperone GRP78 as a major factor in prostate cancer and other malignancies.  Cell surface GRP78 functions as a signaling receptor promoting tumor proliferation and suppressing apoptosis.  Patients with a number of malignancies mount an autoimmune response to GRP78 and these antibodies, which bind to the NH2 terminal domains of GRP78, are receptor agonists whose appearance is a marker of poor prognosis.  More recently, we have shown that antibodies directed against the COOH-terminal domain of GRP78 are receptor antagonists which may have therapeutic potential for treating patients whose tumors express GRP78 on the cell surface.

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