title: Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells.
abstract: In this study, 2-aminophenoxazine-3-one (Phx-3) exhibited a potent cell growth inhibitory effect with apoptotic features in a dose-dependent manner in various cancer cell lines tested. Comparison of the expression profiles of endoplasmic reticulum (ER) stress-related genes in U266 multiple myeloma cells after treatment with Phx-3 and the ER stress inducers tunicamycin (TNM) and thapsigargin (TPG) indicated that although TNM and TPG potently induced pro-apoptotic transcription factor CHOP (GADD153) within 8 h of treatment, Phx-3 induced almost no CHOP within 48 h of treatment in U266 cells. However, murine embryonic fibroblast (MEF) cells and other cancer cell lines (e.g. A549 lung cancer cells and HL-60 acute leukemia cells) exhibited up-regulation of CHOP after treatment with Phx-3. The potency of CHOP induction in response to Phx-3 appeared to be partially correlated with the cytotoxic sensitivity of Phx-3 among various cell lines tested. MEF cells derived from CHOP knockout mice were more resistant to Phx-3 than wild-type MEF cells. Since Phx-3 has been shown to induce activation of NF-κB, a transcription factor functioning as a repressor of CHOP, we further treated U266 cells with a combination of Phx-3 and NF-κB inhibitors (e.g. BAY11-7082 or parthenolide). This enhanced cytotoxicity along with up-modulation of CHOP in U266 cells. These data suggest that ER stress-mediated CHOP induction by Phx-3 is involved in the cytotoxic effect. Regulation of CHOP expression appears to be a potent therapeutic target for cancer treatment.
authors.affiliation: Department of Biochemistry, Tokyo Medical University, Tokyo, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Moriya
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Che
authors.forename: Akio
authors.initials: A
authors.lastname: Tomoda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C497250:Ddit3 protein, mouse; D016328:NF-kappa B; D009570:Nitriles; D010078:Oxazines; D012717:Sesquiterpenes; D013450:Sulfones; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C005512:3-aminophenoxazone; C002669:parthenolide; D019284:Thapsigargin