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Updated: May 16, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis
Ana Slipicevic1, Geir Frode Øy, Anne Katrine Ree Rosnes
1Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. ana.slipicevic@rr-research.no
Abstract:
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells while leaving normal cells unharmed, making it a desirable anticancer target. In the present study, metastatic melanoma cell lines were treated with lexatumumab (Human Genome Sciences, Inc.) a high-affinity monoclonal antibody agonistic to TRAIL receptor 2 (DR5). Binding of the antibody to the receptor led to activation of the extrinsic apoptosis pathway in approximately 20% of the treated cells. However, by combining subtoxic concentrations of the protein translation inhibitor anisomycin with lexatumumab, we obtained synergistic effects on cell viability compared with single agent treatment. Even the low doses of anisomycin could inhibit protein synthesis in melanoma cells with up to 30%, which might result in the shift in the levels of the proteins involved in apoptosis. Co-treatment with anisomycin increased activation of caspases and cleavage of the anti-apoptotic protein Livin, leading to formation of truncated p30-Livin α and p28-Livin β proteins with potential pro-apoptotic functions. Furthermore, ansiomcycin treatment decreased levels of antiapototic XIAP. In summary our results suggest that combinational treatment with anicomycin and lexatumumab represents a novel therapeutic strategy in the treatment of melanoma.
Insights
Combining lexatumumab with anisomycin enhances melanoma cell death. This novel strategy targets apoptosis pathways, offering a potential new treatment for metastatic melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells.
- Lexatumumab is a monoclonal antibody targeting the TRAIL receptor 2 (DR5).
- Metastatic melanoma remains a significant therapeutic challenge.
Purpose of the Study:
- To investigate the synergistic effect of lexatumumab and anisomycin in metastatic melanoma cells.
- To elucidate the molecular mechanisms underlying the combination therapy.
Main Methods:
- Treatment of metastatic melanoma cell lines with lexatumumab and anisomycin.
- Analysis of apoptosis pathway activation, caspase activity, and protein levels.
- Assessment of cell viability and synergistic effects.
Main Results:
- Lexatumumab alone activated apoptosis in ~20% of cells.
- Combination therapy with subtoxic anisomycin concentrations showed synergistic effects on cell viability.
- Anisomycin inhibited protein synthesis, potentially altering apoptosis-related protein levels.
- Co-treatment increased caspase activation and cleavage of anti-apoptotic Livin protein.
- Anisomycin decreased levels of anti-apoptotic XIAP.
Conclusions:
- Combination of anisomycin and lexatumumab is a promising therapeutic strategy for melanoma.
- The synergy involves modulation of apoptosis pathways, including caspase activation and altered expression of apoptosis regulators.
- This approach offers a novel therapeutic avenue for metastatic melanoma treatment.
