title: p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma.
abstract: KILLER/DR5 is a death-domain-containing proapoptotic receptor that binds to the cytotoxic ligand TRAIL. It was originally reported that induction of KILLER/DR5 mRNA following DNA damage was p53-dependent, but some drugs that induce apoptosis can upregulate KILLER/DR5 mRNA expression in cell lines with mutated p53. We further extend those findings by classifying the capability of various apoptosis-inducing drugs to increase the expression of KILLER/DR5 mRNA in a p53-independent manner. beta-Lapachone, a topoisomerase inhibitor, increased KILLER/DR5 mRNA in colon cancer cell lines with wild-type p53 but not with mutant p53. In contrast, betulinic acid, a novel chemotherapeutic compound, induced apoptosis and KILLER/DR5 mRNA in melanoma and glioblastoma cells through a p53-independent mechanism. The synthetic glucocorticoid dexamethasone elevated KILLER/DR5 mRNA in glioblastoma, ovarian cancer, and colon cancer cell lines with mutant p53 undergoing apoptosis, and this induction was inhibited by the transcriptional inhibitor actinomycin D. Although another glucocorticoid, prednisolone, also induced apoptosis, it did not increase KILLER/DR5 mRNA. Finally, the cytokine interferon-gamma (IFN-gamma) induced apoptosis and KILLER/DR5 in cell lines with mutant p53, and the induction of KILLER/DR5 mRNA by IFN-gamma was delayed in cells lacking wild-type STAT1, a transcription factor implicated in IFN-gamma signaling. Similarly, the induction of KILLER/DR5 mRNA by the cytokine TNF-alpha was also delayed in cell lines with mutated STAT1. These findings suggest that KILLER/DR5 may play a role in p53-independent apoptosis induced by specific drugs and warrants further investigation as a novel target for chemotherapy of tumors lacking wild-type p53.
authors.affiliation: Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Meng
authors.forename: W S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism; D009154:Mutation; D009285:Naphthoquinones / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D011239:Prednisolone / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects*; D000094062:Betulinic Acid
chemical_list: D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D009285:Naphthoquinones; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C505639:TNFRSF10B protein, human; D015534:Trans-Activators; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; C014638:beta-lapachone; D003907:Dexamethasone; D007371:Interferon-gamma; D011239:Prednisolone; D000094062:Betulinic Acid