Diallyl trisulfide sensitizes human melanoma cells to TRAIL-induced             cell death by promoting endoplasmic reticulum-mediated apoptosis.
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 poten-tiated 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.
Division of Molecular Cell Immunology and Allergology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan.
Mayumi
M
Murai
Toshio
T
Inoue
Miki
M
Suzuki-Karasaki
Toyoko
T
Ochiai
Chisei
C
Ra
Sigeru
S
Nishida
Yoshihiro
Y
Suzuki-Karasaki
D000498:Allyl Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction; D013440:Sulfides / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
D000498:Allyl Compounds; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013440:Sulfides; D053221:TNF-Related Apoptosis-Inducing Ligand; C042577:diallyl trisulfide; D053454:Caspase 12