Methyl jasmonate down‐regulates survivin expression and sensitizes colon carcinoma cells towards TRAIL‐induced cytotoxicity

• Published in: British journal of pharmacology Vol. 164; no. 5; pp. 1433 - 1444
• Main Authors: Raviv, Z, Zilberberg, A, Cohen, S, Reischer‐Pelech, D, Horrix, C, Berger, MR, Rosin‐Arbesfeld, R, Flescher, E
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2011; Nature Publishing Group
• Subjects: Acetates - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Blotting, Western; Cancer; Cancer therapies; Cell Culture Techniques; Cell Line, Tumor; Cell Survival - drug effects; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; colorectal cancer; Cyclopentanes - pharmacology; Cytochromes c - metabolism; Cytotoxicity; Down-Regulation; Drug Synergism; Flow Cytometry; Gastroenterology. Liver. Pancreas. Abdomen; Genes, Reporter; Humans; Inhibitor of Apoptosis Proteins - biosynthesis; Luciferases - genetics; Medical sciences; methyl jasmonate; Oxylipins - pharmacology; Pharmacology. Drug treatments; Proteins; Receptors, Death Domain - metabolism; Research Papers; Reverse Transcriptase Polymerase Chain Reaction; sensitization; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; survivin; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL; Transfection; Tumors; Rectal disease; TRAIL; Colorectal cancer; Cytotoxicity; methyl jasmonate; Malignant tumor; Survivin; Colonic disease; Cell death; Digestive diseases; Intestinal disease; Sensitization; Colon carcinoma; Tumor cell; Cancer; Apoptosis
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01419.x

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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. CONCLUSION AND IMPLICATIONS 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.