title: Inducement of mitosis delay by cucurbitacin E, a novel tetracyclic triterpene from climbing stem of Cucumis melo L., through GADD45γ in human brain malignant glioma (GBM) 8401 cells.
abstract: Cucurbitacin E (CuE) is a natural compound previously shown to have anti-feedant, antioxidant and antitumor activities as well as a potent chemo-preventive action against cancer. The present study investigates its anti-proliferative property using MTT assay; CuE demonstrated cytotoxic activity against malignant glioma GBM 8401 cells and induced cell cycle G2/M arrest in these cells. CuE-treated cells accumulated in metaphase (CuE 2.5-10 μM) as determined using MPM-2 by flow cytometry. We attempted to characterize the molecular pathways responsible for cytotoxic effects of CuE in GBM 8401 cells. We studied the genome-wide gene expression profile on microarrays and molecular networks by using pathway analysis tools of bioinformatics. The CuE reduced the expression of 558 genes and elevated the levels of 1354 genes, suggesting an existence of the common pathways involved in induction of G2/M arrest. We identified the RB (GADD45β and GADD45γ) and the p53 (GADD45α) signaling pathways as the common pathways, serving as key molecules that regulate cell cycle. Results indicate that CuE produced G2/M arrest as well as the upregulation of GADD45 γ and binding with CDC2. Both effects increased proportionally with the dose of CuE, suggesting that the CuE-induced mitosis delay is regulated by GADD45γ overexpression. Our findings suggest that, in addition to the known effects on cancer prevention, CuE may have antitumor activity in glioma therapy.
authors.affiliation: 1] Graduate Institute of Medical Science, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan [2] Innovative Research Center of Medicine, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Division of Traumatology, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: 1] Graduate Institute of Medical Science, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan [2] Department of Neurosurgery, Tainan Sin-Lau Hospital, Tainan, Taiwan.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Huang
mesh_terms: D050256:Antimitotic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D028463:Cucumis melo / Q000737:chemistry; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D008517:Phytotherapy; D018547:Plant Stems; D010946:Plants, Medicinal; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D015854:Up-Regulation; D000097642:GADD45 Proteins
chemical_list: D050256:Antimitotic Agents; D000972:Antineoplastic Agents, Phytogenic; D016203:CDC2 Protein Kinase; D019926:Cyclin B; D018844:Cyclin-Dependent Kinases; D047908:Intracellular Signaling Peptides and Proteins; D014315:Triterpenes; C485654:GADD45G protein, human; D000097642:GADD45 Proteins; C528899:CDK1 protein, human; C102326:cucurbitacin E