期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 41, 期 6, 页码 2029-2037出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2012.1656
关键词
diallyl trisulfide; melanoma; tumor necrosis factor-related apoptosis-inducing ligand; apoptosis; endoplasmic reticulum
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology [KAKENHI 23591631]
- Nihon University
- Grants-in-Aid for Scientific Research [23591631] Funding Source: KAKEN
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is promising for cancer treatment because of its selective cytotoxicity toward tumor cells. However, some cancer cell types including malignant melanoma cells are resistant to TRAIL cytotoxicity. Here, we show that diallyl trisulfide (DATS), a garlic organosulfur compound, sensitizes melanoma cells to TRAIL-induced apoptosis while sparing normal cells. DATS also potentiates apoptosis induced by agonistic antibodies against death receptors (DR) 4 and DR5. The amplification of DR-mediated apoptosis was associated with increased mitochondrial membrane potential collapse and caspase-3/7 activation. However, these events were not sufficient for full sensitization. TRAIL also induced endoplasmic reticulum (ER) stress, as indicated by the activation of X-box-binding protein 1 and caspase-12 and DATS potentiated both events. Moreover, inhibition of caspase-12, but not caspase-4, abolished the amplification of apoptosis, indicating that ER stress plays a crucial role. On the other hand, DATS and/or TRAIL induced minimal apoptosis and caspase-12 activation in melanocytes despite their substantial expression of DR4 and DR5 on the cell surface. Our data suggest that DATS amplifies death ligand-induced melanoma cell death by disrupting their adaptation to ER-mediated death pathway. The present findings raise the possibility that DATS may be combined with death ligands to treat TRAIL-resistance melanoma cells without impairing its tumor selectivity.
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