title: Methyl jasmonate down-regulates survivin expression and sensitizes colon carcinoma cells towards TRAIL-induced cytotoxicity.
abstract: OBJECTIVE
  Methyl jasmonate (MJ) is a plant stress hormone with selective cytotoxic anti-cancer activities. The TNF-related apoptosis-inducing ligand (TRAIL) death pathway is an attractive target for cancer therapy. Although TRAIL receptors are specifically expressed in primary cancer cells and cancer cell lines, many types of cancer cells remain resistant to TRAIL-induced cytotoxicity. Here we have assessed a possible synergy between MJ and TRAIL cytotoxicity in colorectal cancer (CRC) cell lines.
  
  
  METHODS
  CRC cell lines were pre-incubated with sub-cytotoxic concentrations of MJ followed by TRAIL administration. Cell death was determined by XTT assay and microscopy. Cytochrome c release, caspase cleavage, TRAIL-associated factors, X-linked inhibitor of apoptosis (XIAP) and survivin protein levels were detected by immunoblotting. Survivin transcription was examined by RT-PCR.
  
  
  RESULTS
  Pre-treatment with MJ resulted in increased TRAIL-induced apoptotic cell death, increased cytochrome c release and caspase cleavage. TNFRSF10A, TNFRSF10B, TNFRSF10D, Fas-associated death domain and cellular FLICE-like inhibitory protein remained unchanged during MJ-induced TRAIL sensitization, whereas MJ induced a significant decrease in survivin protein levels. Overexpression of survivin prevented MJ-induced TRAIL cytotoxicity, implying a role for survivin in MJ-induced TRAIL sensitization. MJ decreased survivin mRNA indicating that MJ may affect survivin transcription. In a β-catenin/transcription factor (TCF)-dependent luciferase activity assay, MJ decreased TCF-dependent transcriptional activity.
  
  
  CONCLUSIONS
  MJ, at sub-cytotoxic levels, sensitized CRC cells to TRAIL-induced apoptosis. Thus, combinations of MJ and TRAIL, both selective anti-cancer agents, have potential as novel treatments for CRC.
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. zraviv06@gmail.com
authors.forename: Z
authors.initials: Z
authors.lastname: Raviv
authors.forename: A
authors.initials: A
authors.lastname: Zilberberg
authors.forename: S
authors.initials: S
authors.lastname: Cohen
authors.forename: D
authors.initials: D
authors.lastname: Reischer-Pelech
authors.forename: C
authors.initials: C
authors.lastname: Horrix
authors.forename: M R
authors.initials: MR
authors.lastname: Berger
authors.forename: R
authors.initials: R
authors.lastname: Rosin-Arbesfeld
authors.forename: E
authors.initials: E
authors.lastname: Flescher
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D003517:Cyclopentanes / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D004357:Drug Synergism; D005434:Flow Cytometry; D017930:Genes, Reporter; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis*; D008156:Luciferases / Q000235:genetics; D054883:Oxylipins / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000085:Acetates; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D003517:Cyclopentanes; D051034:Inhibitor of Apoptosis Proteins; D054883:Oxylipins; D053218:Receptors, Death Domain; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D045304:Cytochromes c; C072239:methyl jasmonate; D008156:Luciferases