Journal
APOPTOSIS
Volume 15, Issue 2, Pages 173-182Publisher
SPRINGER
DOI: 10.1007/s10495-009-0430-y
Keywords
Antibody directed against the COOH-terminal domain of GRP78; The unfolded protein response; Apoptosis of cancer cells; The unfolded protein response in prostate cancer; Upregulation of GADD153, PARP-1, and Erdj5; Regulation of IRE-1 alpha, PERK, and ATF6 alpha signaling
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Funding
- NCI NIH HHS [CA131235] Funding Source: Medline
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Receptor-recognized forms of alpha(2)-macroglobulin (alpha M-2*) bind to cancer cell surface GRP78, which functions as a signaling receptor promoting proliferation and survival. Patients with prostate, ovary, and skin cancer may develop auto-antibodies to the alpha M-2* binding site which are receptor agonists whose presence indicates a poor prognosis. By contrast, antibodies directed against the COOH-terminal domain of GPR78 (anti-CTD antibody), are antagonists which down regulate pro-proliferative signaling and upregulate p53. Unfolded protein response (UPR) signaling plays an important role in cell survival and proliferation as well as apoptosis. We, therefore, studied the effect of anti-CTD antibody on UPR signaling in 1-LN and DU-145 prostate cancer cells. Treatment of these cells, which express GRP78 on their cell surface, with this antibody significantly downregulated IRE1-alpha, PERK, and ATF6 alpha-dependent UPR signaling. By contrast, the pro-apoptotic protein GADD153 was elevated. Anti-CTD antibody treatment also elevated apoptotic components, cleaved PARP-1, and Erdj5. In general, a two to threefold effect was observed for the parameters which were studied. These studies suggest that anti-CTD antibody induces growth inhibitory and pro-apoptotic effects by modulating UPR signaling in human prostate cancer cells.
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