title: FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis.
abstract: The anthraquinone compound rhein is a natural agent in the traditional Chinese medicine rhubarb. Preclinical studies demonstrate that rhein has anticancer activity. Treatment of a variety of cancer cells with rhein may induce apoptosis. Here, we report that rhein induces atypical unfolded protein response in breast cancer MCF-7 cells and hepatoma HepG2 cells. Rhein induces CHOP expression, eIF2α phosphorylation and caspase cleavage, while it does not induce glucose-regulated protein 78 (GRP78) expression in both MCF-7 and HepG2 cells. Meanwhile, rhein inhibits thapsigargin-induced GRP78 expression and X box-binding protein 1 splicing. In addition, rhein inhibits Akt phosphorylation and stimulates FOXO transactivation activity. Rhein induces Bim expression in MCF-7 and HepG2 cells, which can be abrogated by FOXO3a knockdown. Knockdown of FOXO3a or Bim abrogates rhein-induced caspase cleavage and apoptosis. The chemical chaperone 4-phenylbutyrate acid antagonizes the induction of FOXO activation, Bim expression and caspase cleavage by rhein, indicating that protein misfolding may be involved in triggering these deleterious effects. We conclude that FOXO3a-mediated up-regulation of Bim is a key mechanism underlying rhein-induced cancer cells apoptosis.
authors.affiliation: School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Wang
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.forename: Yancun
authors.initials: Y
authors.lastname: Yin
authors.forename: Mingjin
authors.initials: M
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Yangfu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000880:Anthraquinones / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019284:Thapsigargin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D010654:Phenylbutyrates; D011518:Proto-Oncogene Proteins; D051742:Transcription Factor CHOP; D019284:Thapsigargin; C075773:4-phenylbutyric acid; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; C020491:rhein