title: Riproximin modulates multiple signaling cascades leading to cytostatic and apoptotic effects in human breast cancer cells.
abstract: BACKGROUND
  Riproximin, a type II ribosome-inactivating protein (RIP), has shown significant cytotoxic effects in diverse types of cancer cells. To better understand its therapeutic potential, elaborated investigations on the mechanistic aspects of riproximin deem crucial. In this study, we focused on riproximin-mediated changes in cellular properties and corresponding molecular pathways in breast cancer cells.
  
  
  METHODS
  Cytotoxicity of riproximin was determined by MTT assay, while the clonogenic and migratory effects were determined by colony formation, migration, and scratch assays. Cytostatic and apoptotic effects were studied by flow cytometry and nuclear staining procedures. Alterations at molecular levels were scrutinized by means of microarray and qRT-PCR methodologies.
  
  
  RESULTS
  Riproximin induced significant cytotoxic effects in the selected human breast cancer cells MDA-MB-231 and MCF-7. Profound inhibition of migration and colony formation were observed in both cell lines in response to riproximin exposure. Concomitantly, a significant arrest in S phase and nuclear fragmentation were observed as causes for its cytostatic and apoptotic effects, respectively. Genetic profiling revealed pronounced induction of the anticancer cytokine IL24/MDA-7 and ER-stress-related GADD genes. In addition, prominent inhibition of the genes relevant to migration (RHO GTPases), anti-apoptotic activities (BCL family), and cell cycle (cyclins) was also noticed.
  
  
  CONCLUSIONS
  Riproximin, with its significant antineoplastic effects, modulates multiple cytostatic and apoptotic pathways in breast cancer cells. Results from these investigations highlight the future therapeutic potential of this naturally occurring compound for breast cancer.
authors.affiliation: Toxicology and Chemotherapy Unit, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Asim
authors.initials: A
authors.lastname: Pervaiz
authors.affiliation: Toxicology and Chemotherapy Unit, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zepp
authors.affiliation: Toxicology and Chemotherapy Unit, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.|German University of Cairo, Cairo, Egypt.
authors.forename: Hassan
authors.initials: H
authors.lastname: Adwan
authors.affiliation: Toxicology and Chemotherapy Unit, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. m.berger@dkfz.de.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Berger
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D010940:Plant Proteins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D010940:Plant Proteins; D012333:RNA, Messenger; C511795:riproximin protein, Ximenia americana
keywords: Apoptosis; Breast cancer; Cytostatic; IL24/MDA-7; Riproximin; Type II RIP