Role of Bcl-xL/Beclin-1 in synergistic apoptotic effects of secretory TRAIL-armed adenovirus in combination with mitomycin C and hyperthermia on colon cancer cells
| Autor: | Dae Hee Lee, Xinxin Song, David L. Bartlett, Seog Young Kim, Yong Tae Kwon, Yong J. Lee |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Hyperthermia
Mitochondria-dependent pathway Cancer Research MAP Kinase Kinase 4 Mitomycin Genetic Vectors Clinical Biochemistry bcl-X Protein Pharmaceutical Science Apoptosis Bcl-xL medicine.disease_cause Adenoviridae TNF-Related Apoptosis-Inducing Ligand Mitomycin C Ad.TRAIL Cell Line Tumor medicine Humans Pharmacology Biochemistry medical Original Paper Antibiotics Antineoplastic biology Cytochrome c Biochemistry (medical) Cytochromes c Membrane Proteins Hyperthermia Induced Cell Biology medicine.disease Molecular biology Mitochondria 3. Good health bcl-2 Homologous Antagonist-Killer Protein Colonic Neoplasms biology.protein Beclin-1 Tumor necrosis factor alpha Protein Multimerization Apoptosis Regulatory Proteins Bcl-2 Homologous Antagonist-Killer Protein |
| Zdroj: | Apoptosis |
| ISSN: | 1360-8185 |
| DOI: | 10.1007/s10495-014-1028-6 |
| Popis: | In this study, we attempted to develop a multimodality approach using chemotherapeutic agent mitomycin C, biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L), and mild hyperthermia to treat colon cancer. For this study, human colon cancer LS174T, LS180, HCT116 and CX-1 cells were infected with secretory TRAIL-armed adenovirus (Ad.TRAIL) and treated with chemotherapeutic agent mitomycin C and hyperthermia. The combinatorial treatment caused a synergistic induction of apoptosis which was mediated through an increase in caspase activation. The combinational treatment promoted the JNK-Bcl-xL-Bak pathway which transmitted the synergistic effect through the mitochondria-dependent apoptotic pathway. JNK signaling led to Bcl-xL phosphorylation at serine 62, dissociation of Bak from Bcl-xL, oligomerization of Bak, alteration of mitochondrial membrane potential, and subsequent cytochrome c release. Overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed the synergistic death effect. Interestingly, Beclin-1 was dissociated from Bcl-xL and overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed dissociation of Beclin-1 from Bcl-xL. A combinatorial treatment of mitomycin C, Ad.TRAIL and hyperthermia induced Beclin-1 cleavage, but the Beclin-1 cleavage was abolished in Beclin-1 double mutant (D133A/D146A) knock-in HCT116 cells, suppressing the apoptosis induced by the combination therapy. We believe that this study supports the application of the multimodality approach to colon cancer therapy. |
| Databáze: | OpenAIRE |
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