Methyl jasmonate down-regulates survivin expression and sensitizes colon carcinoma cells towards TRAIL-induced
Z Raviv1, A Zilberberg, S Cohen
1Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. zraviv06@gmail.com
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.
Insights
Methyl jasmonate (MJ) sensitizes colorectal cancer cells to TNF-related apoptosis-inducing ligand (TRAIL) therapy by reducing survivin. This combination shows potential for novel colorectal cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Methyl jasmonate (MJ) exhibits selective anti-cancer properties.
- TNF-related apoptosis-inducing ligand (TRAIL) pathway is a target for cancer therapy.
- Cancer cell resistance to TRAIL necessitates combination strategies.
Purpose of the Study:
- To investigate the synergistic effects of MJ and TRAIL in colorectal cancer (CRC) cell lines.
- To determine the molecular mechanisms underlying MJ-induced sensitization to TRAIL.
Main Methods:
- CRC cell lines were treated with sub-cytotoxic MJ followed by TRAIL.
- Cell death assessed via XTT assay and microscopy.
- Protein and mRNA levels of apoptosis-related factors, including survivin, were analyzed.
Main Results:
- MJ pre-treatment enhanced TRAIL-induced apoptosis, cytochrome c release, and caspase cleavage.
- MJ significantly decreased survivin protein and mRNA levels.
- Survivin suppression was critical for MJ-induced TRAIL sensitization.
Conclusions:
- Sub-cytotoxic MJ sensitizes colorectal cancer cells to TRAIL-induced apoptosis.
- The combination of MJ and TRAIL presents a promising novel therapeutic approach for colorectal cancer.
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