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Published on: September 11, 2012
Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis
A Hernandez1, R Thomas, F Smith
1Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0536, USA.
Background:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a novel member of the tumor necrosis factor family, induces apoptosis in TRAIL-sensitive tumors through the activation of the caspase pathway. Sodium butyrate (NaBT) induces differentiation and apoptosis in certain colorectal cancers; the molecular mechanisms for these effects have not been clearly defined. The purpose of our study was to determine whether NaBT sensitizes TRAIL-resistant human colon cancer cells to the effects of TRAIL.
Methods:
Human colon cancer cells (KM12C, KML4A, and KM20) that are resistant to TRAIL treatment alone were treated with TRAIL (100 ng/mL), NaBT (5 mmol/L), or a combination of these agents and harvested for total RNA and protein. Western blots were performed to assess intracellular expression of Flice-like inhibitory protein (FLIP), a caspase inhibitor. Percent-specific apoptosis, relative caspase-3 activity, and Annexin-V immunofluorescence were determined at 24 and 48 hours. Cell cycle--related gene expression was assessed by RNase protection.
Results:
Treatment with NaBT for 24 and 48 hours decreased FLIP protein expression in all cell lines. Furthermore, NaBT sensitized these resistant cancer cells to the effects of TRAIL with significant increases noted in cell death, caspase-3 activity, and Annexin-V staining compared with NaBT alone.
Conclusions:
Our findings suggest that the reduction of FLIP protein levels by NaBT renders TRAIL-resistant human colon cancer cells sensitive to TRAIL-mediated apoptosis. The combination of TRAIL with agents (such as NaBT, which target proteins that prevent cell death) may provide a more effective and less toxic regimen for the treatment of resistant colon cancers.
Insights
Sodium butyrate (NaBT) can make TRAIL-resistant colon cancer cells sensitive to TRAIL-induced apoptosis. This combination therapy may offer a more effective treatment for resistant colorectal cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in sensitive tumors via caspase pathway activation.
- Sodium butyrate (NaBT) induces differentiation and apoptosis in colorectal cancers, but mechanisms are unclear.
- TRAIL-resistant colon cancer cells pose a therapeutic challenge.
Purpose of the Study:
- To investigate if NaBT sensitizes TRAIL-resistant human colon cancer cells to TRAIL.
- To elucidate the molecular mechanisms underlying NaBT's effects on TRAIL sensitivity.
Main Methods:
- Human colon cancer cell lines resistant to TRAIL were treated with TRAIL, NaBT, or both.
- Western blots assessed FLICE-inhibitory protein (FLIP) expression.
- Apoptosis, caspase-3 activity, and Annexin-V staining were quantified.
- Cell cycle gene expression was analyzed via RNase protection.
Main Results:
- NaBT treatment significantly reduced FLIP protein expression in all tested colon cancer cell lines.
- NaBT sensitized TRAIL-resistant cells to TRAIL-induced apoptosis.
- Combined treatment showed increased cell death, caspase-3 activity, and Annexin-V staining compared to NaBT alone.
Conclusions:
- NaBT enhances TRAIL sensitivity in resistant colon cancer by downregulating FLIP.
- Combining TRAIL with NaBT presents a promising strategy for treating resistant colorectal cancers.
- This combination may offer a more effective and less toxic therapeutic regimen.
