Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME.
Stress protein GRP78/BiP is highly induced in progressively growing tumors and has recently been shown to exert a protective role against lysis by cytotoxic T cells and tumor necrosis factor in vitro. This raises the question whether the in vitro observed protective function of GRP78/BiP translates into the in vivo situation in which tumors grow progressively, killing the host. Herein we report that molecular inhibition of GRP78/BiP induction in the fibrosarcoma B/C10ME, while not affecting in vitro cell proliferation, causes a dramatic increase in apoptotic cell death upon Ca2+ depletion of the endoplasmic reticulum. When B/C10ME cells incapable of inducing GRP78/BiP are injected into mice, tumors are initially formed that, however, regress presumably due to a cytotoxic T-cell response demonstrable by a strong in vitro response to the tumor with spleen cells of regressor mice. Since sensitivity to apoptosis is key to tumor rejection, these results may point to new approaches to the therapy of cancer via regulation of stress protein GRP78/BiP.
Jamora
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C
Department of Biochemistry and Molecular Biology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Dennert
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G
Lee
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AS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000096:biosynthesis*; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005354:Fibrosarcoma / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D007156:Immunologic Memory; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000096:biosynthesis*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium