title: Diallyl trisulfide induces apoptosis of human basal cell carcinoma cells via endoplasmic reticulum stress and the mitochondrial pathway.
abstract: Diallyl trisulfide (DATS), an active component of garlic oil, has attracted much attention because of its anticancer effect on several types of cancers. However, the mechanism of DATS-induced apoptosis of basal cell carcinoma (BCC) is not fully understood. In the present study, we revealed that DATS-mediated dose-dependent induction of apoptosis in BCC cells was associated with intracellular reactive oxygen species accumulation and disrupted mitochondrial membrane potential. Western analysis demonstrated concordant expression of molecules involved in mitochondrial apoptosis, including DATS-associated increases in phospho-p53, proapoptotic Bax, and decreases in antiapoptotic Bcl-2 and Bcl-xl in BCC cells. Moreover, DATS induced the release of cytochrome c, apoptosis-inducing factor, and HtrA2/Omi into the cytoplasm, and activated factors downstream of caspase-dependent and caspase-independent apoptosis, including nuclear translocation of apoptotic-inducing factor and endonuclease G and the caspase cascade. These results were confirmed by pretreatment with the antioxidant N-acetyl-L-cysteine and the caspase inhibitor (z-VAD-fmk), the latter of which did not completely enhance the viability of DATS-treated BBC cells. Exposure to DATS additionally induced endogenous endoplasmic reticulum stress markers and intracellular Ca2⁺ mobilization, upregulation of Bip/GRP78 and CHOP/GADD153, and activation of caspase-4. Our findings suggest that DATS exerts chemopreventive potential via ER stress and the mitochondrial pathway in BCC cells.
authors.affiliation: Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsiao-Chi
authors.initials: HC
authors.lastname: Wang
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Hsieh
authors.forename: Jen-Hung
authors.initials: JH
authors.lastname: Yang
authors.forename: Shuw-Yuan
authors.initials: SY
authors.lastname: Lin
authors.forename: Lee-Yan
authors.initials: LY
authors.lastname: Sheen
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053144:Cell Nucleus Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004706:Endodeoxyribonucleases / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013440:Sulfides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000498:Allyl Compounds; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D015853:Cysteine Proteinase Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D017382:Reactive Oxygen Species; D013440:Sulfides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C042577:diallyl trisulfide; D004706:Endodeoxyribonucleases; C052391:endonuclease G