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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.
Abstract
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.
Type
Journal articleSubject
AdenocarcinomaAmino Acid Sequence
Antibodies, Monoclonal
Antigens, Neoplasm
Antigens, Surface
Caspases
Cell Line, Tumor
Enzyme Activation
Gene Knockdown Techniques
Heat-Shock Proteins
Humans
MAP Kinase Signaling System
Male
Mitogen-Activated Protein Kinases
Molecular Sequence Data
Neoplasm Proteins
Phosphatidylinositol 3-Kinases
Prostatic Neoplasms
Protein Kinases
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt
Signal Transduction
Transcription, Genetic
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https://hdl.handle.net/10161/3961Collections
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Show full item recordScholars@Duke
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
- Prost
Salvatore Vincent Pizzo
Distinguished Professor of Pathology, in the School of Medicine
RESEARCH ABSTRACT 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 appearanc
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